U.S. patent application number 10/580088 was filed with the patent office on 2007-08-16 for antibacterial agents.
This patent application is currently assigned to Warner Lambert Company LLC. Invention is credited to Edmund Lee Ellsworth, Denton Wade Hoyer, Kim Marie Hutchings, Jackie Diane Kendall, Sean Timothy Murphy, Jeremy Tyson Starr, Tuan Phong Tran.
Application Number | 20070191333 10/580088 |
Document ID | / |
Family ID | 34623168 |
Filed Date | 2007-08-16 |
United States Patent
Application |
20070191333 |
Kind Code |
A1 |
Hutchings; Kim Marie ; et
al. |
August 16, 2007 |
Antibacterial agents
Abstract
Compounds of formula I and methods for their preparation are
disclosed. Further disclosed are methods of making biologically
active compounds of formula I as well as pharmaceutically
acceptable compositions comprising compounds of formula I.
Compounds of formula I as disclosed herein can be used in a variety
of applications including use as antibacterial agents.
Inventors: |
Hutchings; Kim Marie; (Ann
Arbor, MI) ; Kendall; Jackie Diane; (Newmarket,
NZ) ; Murphy; Sean Timothy; (Ypsilanti, MI) ;
Tran; Tuan Phong; (Canton, MI) ; Ellsworth; Edmund
Lee; (Pinckney, MI) ; Hoyer; Denton Wade;
(Dexter, MI) ; Starr; Jeremy Tyson; (Ann Arbor,
MI) |
Correspondence
Address: |
PFIZER INC.
PATENT DEPARTMENT, MS8260-1611
EASTERN POINT ROAD
GROTON
CT
06340
US
|
Assignee: |
Warner Lambert Company LLC
|
Family ID: |
34623168 |
Appl. No.: |
10/580088 |
Filed: |
November 18, 2004 |
PCT Filed: |
November 18, 2004 |
PCT NO: |
PCT/IB04/03645 |
371 Date: |
February 27, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60523072 |
Nov 18, 2003 |
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60606442 |
Sep 2, 2004 |
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Current U.S.
Class: |
514/210.05 ;
514/266.3; 514/81; 544/244; 544/253; 544/286 |
Current CPC
Class: |
A61P 9/10 20180101; A61P
9/12 20180101; A61P 1/02 20180101; A61P 17/02 20180101; A61P 27/02
20180101; A61P 19/08 20180101; A61P 27/16 20180101; A61P 17/00
20180101; A61P 25/00 20180101; C07D 471/04 20130101; C07F 9/65583
20130101; A61P 11/04 20180101; C07F 9/6561 20130101; A61P 19/02
20180101; C07F 9/65128 20130101; A61P 13/02 20180101; A61P 31/00
20180101; A61P 15/00 20180101; A61P 9/14 20180101; C07D 413/14
20130101; A61P 43/00 20180101; A61P 29/00 20180101; A61P 1/04
20180101; C07D 403/04 20130101; A61P 31/04 20180101 |
Class at
Publication: |
514/210.05 ;
544/253; 514/081; 544/244; 514/266.3; 544/286 |
International
Class: |
A61K 31/675 20060101
A61K031/675; A61K 31/495 20060101 A61K031/495; A61K 31/517 20060101
A61K031/517; C07F 9/6512 20060101 C07F009/6512; C07D 239/88
20060101 C07D239/88 |
Claims
1. A compound of formula I: ##STR512## or a pharmaceutically
acceptable salt thereof, wherein: X is N or C, provided that when X
is N, R.sub.5 is absent at that position; R.sub.1 is
(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.6)Cycloalkyl, halo(C.sub.3-C.sub.6)cycloalkyl aryl,
and heteroaryl; CH.sub.2(C.sub.3-C.sub.6)cycloalkyl; R.sub.2 is H,
NH.sub.2, ##STR513## NH(C.sub.1-C.sub.6)alkyl,
NH(C.sub.3-C.sub.6)cycloalkyl, NH-aryl, NH-heteroaryl,
NHSO.sub.2--(C.sub.1-C.sub.6)alkyl, NHSO.sub.2-aryl,
NHSO.sub.2-heteroaryl, ##STR514## wherein g is an integer from 1 to
10, Q is O, NH, or is absent, and R.sub.2a and R.sub.2a' are each
independently H or (C.sub.1-C.sub.6)alkyl, or taken together with
the carbons to which they are attached form a 3, 4, 5, or
6-membered substituted or unsubstituted ring, and R.sub.2b is
(C.sub.1-C.sub.6)alkyl, aryl, or heteroaryl, ##STR515## wherein
R.sub.2a and R.sub.2a' are as defined above, ##STR516## wherein
indicates the point of attachment, p is 0 or 1, and R.sub.2c is H,
(C.sub.1-C.sub.6)alkyl, O(C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.7)cycloalkyl, aryl, heterocyclo, heteroaryl, or
##STR517## wherein R.sub.2a, R.sub.2b, and Q, are as defined above,
and h and n are each independently integers from 0 to 10, and Y is
OH, OPO(OH).sub.2, OPO(O(C.sub.1-C.sub.6)).sub.2, or
NR.sub.2dR.sub.2e, wherein R.sub.2d and R.sub.2e are each
independently H, (C.sub.1-C.sub.6)alkyl, or
(C.sub.3-C.sub.7)cycloalkyl, ##STR518## wherein q is 0 or 1,
R.sub.2f and R.sub.2f' are each independently H,
(C.sub.1-C.sub.6)alkyl, aryl, or heteroaryl, or taken together with
the carbon to which they are attached form a 3, 4, 5, or 6 membered
substituted or unsubstituted ring, and R.sub.2g is
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl, or
heterocyclo, or heteroaryl; R.sub.3, R.sub.4, and R.sub.5 are each
independently H, halo, NH.sub.2, (C.sub.1-C.sub.6)alkyl,
halo(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, or
halo(C.sub.1-C.sub.6)alkoxy nitrile; or R.sub.1 and R.sub.5 taken
together with the carbons to which they are attached form a
substituted or unsubstituted 5- or 6-membered substituted or
unsubstituted ring containing 0, 1, or 2 heteroatoms selected from
O, S, SO, SO.sub.2, or NR.sub.x, wherein R.sub.x is H or
(C.sub.1-C.sub.6)alkyl; and A is ##STR519## wherein z is 0, 1, or 2
and q is 0, 1, 2, or 3; R.sub.a and R.sub.b are each independently
H, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
halo(C.sub.1-C.sub.6)alkyl, halo, or R.sub.a and R.sub.b taken
together with the carbon to which they are attached form C.dbd.O,
C.dbd.NO(C.sub.1-C.sub.6)alkyl, or a 3, 4, 5 or 6-membered
substituted or unsubstituted ring; R', R'', R''', and R'''' are
each independently H, (C.sub.1-C.sub.6)alkyl,
--O(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, aryl, or
heteroaryl; and B is ##STR520## provided that when B is ##STR521##
R' is not --O(C.sub.1-C.sub.6)alkyl, and wherein " " indicates the
point of attachment; R.sub.c and R.sub.d are each independently H,
(C.sub.6-C.sub.6)alkylnitrile; ##STR522## (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.6)cycloalkyl, heteroaryl,
SO.sub.2--(C.sub.1-C.sub.6)alkyl, SO.sub.2-aryl,
SO.sub.2-heteroaryl, ##STR523## wherein g is an integer from 1 to
10, Q is as defined above, and R.sub.2a and R.sub.2a' are each
independently H or (C.sub.1-C.sub.6)alkyl, or taken together with
the carbons to which they are attached form a 3, 4, 5, or
6-membered substituted or unsubstituted ring, and R.sub.2b is
(C.sub.1-C.sub.6)alkyl, aryl, or heteroaryl, ##STR524## wherein
R.sub.2a and R.sub.2a' are as defined above, ##STR525## wherein
indicates the point of attachment, p is 0 or 1, and R.sub.2c is H,
(C.sub.1-C.sub.6)alkyl, O(C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.7)cycloalkyl, aryl, heterocyclo, heteroaryl, or
##STR526## wherein R.sub.2a, R.sub.2b, and Q are as defined above,
and h and j are each independently integers from 0 to 10, and Y is
OH, OPO(OH).sub.2, OPO(O(C.sub.1-C.sub.6)).sub.2, or
NR.sub.2dR.sub.2e, wherein R.sub.2d and R.sub.2e are each
independently H, (C.sub.1-C.sub.6)alkyl, or
(C.sub.3-C.sub.7)cycloalkyl, ##STR527## wherein q is 0 or 1,
R.sub.2f and R.sub.2f' are each independently H,
(C.sub.1-C.sub.6)alkyl, aryl, or heteroaryl, or taken together with
the carbon to which they are attached form a 3, 4, 5, or 6 membered
substituted or unsubstituted ring, and R.sub.2g is
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.7)cycloalkyl, aryl, or
heterocyclo, or heteroaryl; R.sub.e , and R.sub.f are each
independently X, C.sub.1-C.sub.6 alkyl, haloalkyl, halo, or R.sub.e
and R.sub.f taken together with the carbon to which they are
attached form a 3, 4, 5 or 6-membered substituted or unsubstituted
ring; R.sub.g and R.sub.h are each independently H, C.sub.1-C.sub.6
alkyl, haloalkyl, or taken together with the carbon to which they
are attached to form a 3, 4, 5 or 6-membered substituted or
unsubstituted ring; and R.sub.j and R.sub.k, are each independently
H, (C.sub.1-C.sub.6)alkyl, haloalkyl,
(C.sub.1-C.sub.6)alkyl-NR.sub.cR.sub.d,
(C.sub.1-C.sub.6)alkyl-OR.sub.c, aryl, heteroaryl, heterocycle,
##STR528## wherein Z is O or NR.sub.c, or R.sub.j and R.sub.k taken
together with the carbon to which they are attached to form a 3, 4,
5 or 6-membered substituted or unsubstituted ring.
2. The compound of claim 1, wherein X is C or N; R.sub.1 is
(C.sub.1-C.sub.6)cycloalkyl and halo(C.sub.1-C.sub.6)cycloalkyl,
aryl, or heteroaryl; R.sub.3 is H or NH.sub.2; R.sub.4 is H or
halo; R.sub.5 is halo, methyl, trifluoromethyl, methoxy,
fluoromethoxy, difluoromethoxy, or trifluoromethoxy when X is
C.
3. The compound of claim 2, wherein X is C or N; R.sub.1 is
cyclopropyl or fluorocyclopropyl; R.sub.3 is H or NH.sub.2; R.sub.4
is H or F; R.sub.5 is halo, methyl, or methoxy.
4. The compound of claim 1, wherein R.sub.1, R.sub.3, and R.sub.5
are as provided in the following structures, and R.sub.2 is
NH.sub.2 or H, and R.sub.4 is H or F: ##STR529## ##STR530##
##STR531## ##STR532##
5. The compound of claim 1, wherein z is 0, 1, 2, when q is 2 or 3
or z is 1 or 2 when q is 0, 1, 2, or 3; R.sub.a and R.sub.b are
each independently H, methyl, ethyl, fluoro, fluoromethyl,
trifluoromethyl, fluorethyl, methoxy, MeO--N, or taken together
with the carbons to which they are attached form a cyclopropyl
ring; R', R'', R''', and R'''' each independently H, fluoro,
methyl, ethyl, fluoromethyl, fluoroethyl, phenyl, benzyl, or
methoxy; R.sub.c and R.sub.d each independently are H, methyl, or
ethyl; R.sub.e and R.sub.f each independently are H, methyl, or
ethyl; R.sub.g and R.sub.h each independently are H, methyl, ethyl,
fluoromethyl, difluoromethyl, trifluoroethyl, cyclopropyl, phenyl,
isoxazolyl, carboxymethyl, carboxyethyl, or ##STR533## or taken
together with the carbons to which they are attached form .DELTA.;
and R.sub.j and R.sub.k each independently are H, methyl, ethyl,
fluoromethyl, difluoromethyl, trifluoroethyl, cyclopropyl, phenyl,
isoxazolyl, carboxymethyl, carboxyethyl, or ##STR534## or taken
together with the carbons to which they are attached form
.DELTA..
6. The compound of claim 1, wherein A is ##STR535## and z is 0, 1,
or 2, selected from the group consisting of: ##STR536## ##STR537##
wherein indicates the point of attachment, or A is ##STR538##
wherein z is 0, 1, or 2 and q is 0, 1, 2, or 3, selected from the
group consisting of: ##STR539## wherein indicates the point of
attachment.
7. The compound of claim 6, wherein B is ##STR540## or ##STR541##
and is selected from the group consisting of: ##STR542## ##STR543##
wherein indicates the point of attachment.
8. The compound of claim 6, wherein ##STR544## is selected from the
group consisting of: ##STR545## ##STR546## ##STR547## ##STR548##
wherein R is CH.sub.2CH.sub.2CN and wherein indicates the point of
attachment.
9. The compound of claim 6, wherein ##STR549## is selected from the
group consisting of: ##STR550## ##STR551## wherein R is CH.sub.2CN,
and wherein indicates the point of attachment.
10. The compound of claim 6, wherein ##STR552## is selected from
the group consisting of: ##STR553## wherein R is
CH.sub.2CH.sub.2CN, and wherein indicates the point of
attachment.
11. The compound of claim 6, wherein ##STR554## is selected from
the group consisting of: ##STR555## wherein R.sub.c is H or
(C.sub.1-C.sub.6)alkyl, R is CH.sub.2CN, and wherein indicates the
point of attachment.
12. The compound of claim 1, which is a compound of formulas II,
III, IV, V, or VI: ##STR556##
13. The compound, or a pharmaceutically acceptable salt thereof, of
claim 1 selected from the group consisting of:
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahy-
dro-quinazolin-7-yl)-pyrrolidin-3-ylmethyl]-amino}-propionitrile;
3-{[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quin-
azolin-7-yl)-pyrrolidin-3-ylmethyl]-amino}-propionitrile;
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-pyrrolidin-3-ylmethyl]-amino}-propionitrile;
3-{1-[1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinaz-
olin-7-yl)-pyrrolidin-3-ylmethyl]-amino}-propionitrile;
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahy-
dro-quinazolin-7-yl)-pyrrolidin-3-yl]-ethyl]-methyl-amino]-propionitrile;
3-{[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quin-
azolin-7-yl)-pyrrolidin-3-ylmethyl]-methyl-amino}-propionitrile;
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-pyrrolidin-3-ylmethyl]-methyl-amino}-propionitrile;
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-pyrrolidin-3-ylmethyl]-methyl-amino}-propionitrile;
3-{1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-pyrrolidin-3-yl]-ethyl amino}-propionitrile;
3-{1-[1(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-qui-
nazolin-7-yl)-pyrrolidin-3-yl]-ethylamino}-propionitrile;
3-{1-[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-qui-
nazolin-7-yl)-pyrrolidin-3-yl]-ethylamino}-propionitrile;
3-({1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetr-
ahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-ethyl}-methyl-amino)-propionitril-
e;
3-({1-[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydr-
o-quinazolin-7-yl)-pyrrolidin-3-yl]-ethyl}-methyl-amino)-propionitrile;
3-({1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-pyrrolidin-3-yl]-ethyl}-methyl-amino)-propionitrile-
;
3-({1-[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro--
quinazolin-7-yl)-pyrrolidin-3-yl]-ethyl}-methyl-amino)-propionitrile;
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahy-
dro-quinazolin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-amino}-propionitrile;
3-{[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-qui-
nazolin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-amino}-propionitrile;
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-amino}-propionitrile;
3-{[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quina-
zolin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-amino}-propionitrile;
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahy-
dro-quinazolin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-methyl-amino}-propion-
itrile;
3-{[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahy-
dro-quinazolin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-methyl-amino}-propion-
itrile;
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4--
tetrahydro-quinazolin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-methyl-amino}--
propionitrile;
3-{[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quina-
zolin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-methyl-amino}-propionitrile;
3-{1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-pyrrolidin-3-yl]-cyclopropylamino}-propionitrile;
3-.ident.1-[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahy-
dro-quinazolin-7-yl)-pyrrolidin-3-yl]-cyclopropylamino}-propionitrile;
3-{1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrah-
ydro-quinazolin-7-yl)-pyrrolidin-3-yl]-cyclopropylamino}-propionitrile;
3-{1-[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-qui-
nazolin-7-yl)-pyrrolidin-3-yl]-cyclopropylamino}-propionitrile;
3-({1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetr-
ahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-cyclopropyl}-methyl-amino)-propio-
nitrile;
3-({1-[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tet-
rahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-cyclopropyl}-methyl-amino)-propi-
onitrile;
3-({1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2-
,3,4-tetrahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-cyclopropyl}-methyl-amin-
o)-propionitrile;
3-({1-[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-qu-
inazolin-7-yl)-pyrrolidin-3-yl]-cyclopropyl}-methyl-amino)-propionitrile;
N-[2-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-pyrrolidin-3-yl]-2-(2-cyano-ethylamino)-ethyl]-acet-
amide;
N-[2-[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrah-
ydro-quinazolin-7-yl)-pyrrolidin-3-yl]-2-(2-cyano-ethylamino)-ethyl]-aceta-
mide;
N-[2-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4--
tetrahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-2-(2-cyano-ethylamino)-ethyl]-
-acetamide;
N-[2-[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-qui-
nazolin-7-yl)-pyrrolidin-3-yl]-2-(2-cyano-ethylamino)-ethyl]-acetamide;
N-{2-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-pyrrolidin-3-yl]-2-[(2-cyano-ethyl)-methyl-amino]-e-
thyl}-acetamide;
N-{2-[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-qu-
inazolin-7-yl)-pyrrolidin-3-yl]-2-[(2-cyano-ethyl)-methyl-amino]-ethyl}-ac-
etamide;
N-{2-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3-
,4-tetrahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-2-[(2-cyano-ethyl)-methyl--
amino]-ethyl}-acetamide;
N-{2-[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-qui-
nazolin-7-yl)-pyrrolidin-3-yl]-2-[(2-cyano-ethyl)-methyl-amino]-ethyl}-ace-
tamide;
3-{[1-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-pyrrolidin-3-ylmethyl]-amino}-propionitrile;
3-{[1-(1-Cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7--
yl)-pyrrolidin-3-ylmethyl]-amino}-propionitrile;
3-{[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinaz-
olin-7-yl)-pyrrolidin-3-ylmethyl]-amino}-propionitrile.
3-{[1-(1-Cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-y-
l)-pyrrolidin-3-ylmethyl]-amino}-propionitrile;
3-{[1-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quina-
zolin-7-yl)-pyrrolidin-3-ylmethyl]-methyl-amino}-propionitrile; and
3-{[1-(1-Cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7--
yl)-pyrrolidin-3-ylmethyl]-methyl-amino}-propionitrile.
14. The compound, or a pharmaceutically acceptable salt thereof, of
claim 1 selected from the group consisting of:
3-{[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinaz-
olin-7-yl)-pyrrolidin-3-ylmethyl]-methyl-amino-}-propionitrile;
3-{[1-(1-Cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-y-
l)-pyrrolidin-3-ylmethyl]-methyl-amino}-propionitrile;
3-{1-[1-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-qui-
nazolin-7-yl)-pyrrolidin-3-yl]-ethylamino}-propionitrile;
3-{1-[1-(1-Cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin--
7-yl)-pyrrolidin-3-yl]-ethylamino}-propionitrile;
3-{1-[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quin-
azolin-7-yl)-pyrrolidin-3-yl]-ethylamino}-propionitrile;
3-{1-[1-(1-Cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-
-yl)-pyrrolidin-3-yl]-ethylamino}-propionitrile;
3-({1-[1-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-qu-
inazolin-7-yl)-pyrrolidin-3-yl]-ethyl}-methyl-amino)-propionitrile;
3-({1-[1-(1-Cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-
-7-yl)-pyrrolidin-3-yl]-ethyl}-methyl-amino)-propionitrile;
3-({1-[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-qui-
nazolin-7-yl)-pyrrolidin-3-yl]-ethyl}-ethyl-amino)-propionitrile;
3-({1-[1-(1-Cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin--
7-yl)-pyrrolidin-3-yl]-ethyl}-ethyl-amino)-propionitrile;
3-{[1-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quina-
zolin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-amino}-propionitrile;
3-{[1-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quina-
zolin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-amino}-propionitrile;
3-{[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinaz-
olin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-amino}-propionitrile;
3-{[1-(1-Cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-y-
l)-3-methyl-pyrrolidin-3-ylmethyl]-amino}-propionitrile;
3-{[1-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quina-
zolin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-methyl-amino}-propionitrile;
3-{[1-(1-Cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7--
yl)-3-methyl-pyrrolidin-3-ylmethyl]-methyl-amino}-propionitrile;
3-{[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinaz-
olin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-methyl-amino}-propionitrile;
3-{[1-(1-Cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-y-
l)-3-methyl-pyrrolidin-3-ylmethyl]-methyl-amino}-propionitrile;
3-{1-[1-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-qui-
nazolin-7-yl)-pyrrolidin-3-yl]-cyclopropylamino}-propionitrile;
3-{1-[1-(1-Cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin--
7-yl)-pyrrolidin-3-yl]-cyclopropylamino}-propionitrile;
3-{1-[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quin-
azolin-7-yl)-pyrrolidin-3-yl]-cyclopropylamino}-propionitrile;
3-{1-[1-(1-Cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-
-yl)-pyrrolidin-3-yl]-cyclopropylamino}-propionitrile;
3-({1-[1-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-qu-
inazolin-7-yl)-pyrrolidin-3-yl]-cyclopropyl}-methyl-amino)-propionitrile;
3-({1-[1-(1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-
-7-yl)-pyrrolidin-3-yl]-cyclopropyl}-methyl-amino)-propionitrile;
3-({1-[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-qui-
nazolin-7-yl)-pyrrolidin-3-yl]-cyclopropyl}-methyl-amino)-propionitrile;
3-({1-[1-(1-Cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin--
7-yl)-pyrrolidin-3-yl]-cyclopropyl}-methyl-amino)-propionitrile;
N-[2-[1-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-qui-
nazolin-7-yl)-pyrrolidin-3-yl]-2-(2-cyano-ethylamino)-ethyl]-acetamide;
N-[2-[1-(1-Cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin--
7-yl)-pyrrolidin-3-yl]-2-(2-cyano-ethylamino)-ethyl]-acetamide;
N-[2-[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quin-
azolin-7-yl)-pyrrolidin-3-yl]-2-(2-cyano-ethylamino)-ethyl]-acetamide;
N-[2-[1-(1-Cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-
-yl)-pyrrolidin-3-yl]-2-(2-cyano-ethylamino)-ethyl]-acetamide;
N-{2-[1-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-qui-
nazolin-7-yl)-pyrrolidin-3-yl]-2-[(2-cyano-ethyl)-methyl-amino]-ethyl}-ace-
tamide;
N-{2-[1-(1-Cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-qui-
nazolin-7-yl)-pyrrolidin-3-yl]-2-[(2-cyano-ethyl)-methyl-amino]-ethyl}-ace-
tamide;
N-{2-[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahy-
dro-quinazolin-7-yl)-pyrrolidin-3-yl]-2-[(2-cyano-ethyl)-methyl-amino]-eth-
yl}-acetamide;
N-{2-[1-(1-Cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-
-yl)-pyrrolidin-3-yl]-2-[(2-cyano-ethyl)-methyl-amino]-ethyl}-acetamide;
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahy-
dro-quinazolin-7-yl)-pyrrolidin-3-ylmethyl]-amino}-butyronitrile;
3-{[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quin-
azolin-7-yl)-pyrrolidin-3-ylmethyl]-amino}-butyronitrile;
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-pyrrolidin-3-ylmethyl]-amino}-butyronitrile;
3-{[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quina-
zolin-7-yl)-pyrrolidin-3-ylmethyl]-amino}-butyronitrile;
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahy-
dro-quinazolin-7-yl)-pyrrolidin-3-ylmethyl]-methyl-amino}-butyronitrile;
3-{[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quin-
azolin-7-yl)-pyrrolidin-3-ylmethyl]-methyl-amino}-butyronitrile;
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-pyrrolidin-3-ylmethyl]-methyl-amino}-butyronitrile;
3-{[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quina-
zolin-7-yl)-pyrrolidin-3-ylmethyl]-methyl-amino}-butyronitrile;
3-[5-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-5-aza-spiro[2.4]hept-1-ylamino]-propionitrile;
3-[5-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quina-
zolin-7-yl)-5-aza-spiro[2.4]hept-1-ylamino]-propionitrile; and
3-[5-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydr-
o-quinazolin-7-yl)-5-aza-spiro[2.4]hept-1-ylamino]-propionitrile.
15. The compound, or a pharmaceutically acceptable salt thereof of
claim 1 selected from the group consisting of:
3-[5-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinaz-
olin-7-yl)-5-aza-spiro[2.4]hept-1-ylamino]-propionitrile;
3-{1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-azetidin-3-yl]-propylamino}-propionitrile;
3-{1-[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-qu-
inazolin-7-yl)-azetidin-3-yl]-propylamino}-propionitrile;
3-{1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrah-
ydro-quinazolin-7-yl)-azetidin-3-yl]-propylamino}-propionitrile;
3-{1-[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-qui-
nazolin-7-yl)-azetidin-3-yl]-propylamino}-propionitrile;
3-({1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetr-
ahydro-quinazolin-7-yl)-azetidin-3-yl]-propyl}-methyl-amino)-propionitrile-
.
3-({1-[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-
-quinazolin-7-yl)-azetidin-3-yl]-propyl}-methyl-amino)-propionitrile;
3-({1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-azetidin-3-yl]-propyl}-methyl-amino)-propionitrile;
3-({1-[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-q-
uinazolin-7-yl)-azetidin-3-yl]-propyl}-methyl-amino)-propionitrile;
3-{1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-azetidin-3-yl]-cylopropylamino}-propionitrile;
3-{1-[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-qu-
inazolin-7-yl)-azetidin-3-yl]-cyclopropylamino}-propionitrile;
3-{1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrah-
ydro-quinazolin-7-yl)-azetidin-3-yl]-cyclopropylamino}-propionitrile;
3-{1-[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-qui-
nazolin-7-yl)-azetidin-3-yl]-cyclopropylamino}-propionitrile;
3-({1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetr-
ahydro-quinazolin-7-yl)-azetidin-3-yl]-cyclopropyl}-methyl-amino)-propioni-
trile;
3-({1-[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-azetidin-3-yl]-cyclopropyl}-methyl-amino)-propionit-
rile;
3-({1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-
-tetrahydro-quinazolin-7-yl)-azetidin-3-yl]-cyclopropyl}-methyl-amino)-pro-
pionitrile;
3-({1-[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-qu-
inazolin-7-yl)-azetidin-3-yl]-cyclopropyl)-methyl-amino)-propionitrile;
3-({1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetr-
ahydro-quinazolin-7-yl)-azetidin-3-yl]-cyclopropyl}-ethyl-amino)-propionit-
rile;
3-({1-[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrah-
ydro-quinazolin-7-yl)-azetidin-3-yl]-cyclopropyl}-ethyl-amino)-propionitri-
le;
3-({1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-t-
etrahydro-quinazolin-7-yl)-azetidin-3-yl]-cyclopropyl}ethyl-amino)-propion-
itrile;
3-({1-[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-azetidin-3-yl]-cyclopropyl}-ethyl-amino)-propionitr-
ile;
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-te-
trahydro-quinazolin-7-yl)-pyrrolidin-3-ylmethyl]-ethyl-amino}-propionitril-
e;
3-{[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-q-
uinazolin-7-yl)-pyrrolidin-3-ylmethyl]-ethyl-amino}-propionitrile;
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-pyrrolidin-3-ylmethyl]-ethyl-amino}-propionitrile;
3-{[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quina-
zolin-7-yl)-pyrrolidin-3-ylmethyl]-ethyl-amino}-propionitrile;
3-({1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetr-
ahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-ethyl}-ethyl-amino)-propionitrile-
;
3-({1-[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-
-quinazolin-7-yl)-pyrrolidin-3-yl]-ethyl}-ethyl-amino)-propionitrile;
3-({1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-pyrrolidin-3-yl]-ethyl}-ethyl-amino)-propionitrile;
3-({1-[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-q-
uinazolin-7-yl)-pyrrolidin-3-yl]-ethyl}-ethyl-amino)-propionitrile;
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahy-
dro-quinazolin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-ethyl-amino}-propioni-
trile;
3-{[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-ethyl-amino}-propionit-
rile;
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-te-
trahydro-quinazolin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-ethyl-amino}-pro-
pionitrile;
3-{[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quina-
zolin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-ethyl-amino}-propionitrile;
3-({1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetr-
ahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-cyclopropyl}-ethyl-amino)-propion-
itrile;
3-({1-[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetr-
ahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-cyclopropyl}-ethyl-amino)-propion-
itrile;
3-({1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3-
,4-tetrahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-cyclopropyl}-ethyl-amino)--
propionitrile;
3-({1-[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-qu-
inazolin-7-yl)-pyrrolidin-3-yl]-cyclopropyl}-ethyl-amino)-propionitrile;
N-{2-[1-(3-Amino-1-cyclopropyl-6-fluoro-5-methoxy-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-pyrrolidin-3-yl]-2-[(2-cyano-ethyl)-ethyl-amino]-et-
hyl}-acetamide;
N-{2-[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-qu-
inazolin-7-yl)-pyrrolidin-3-yl]-2-[(2-cyano-ethyl)-ethyl-amino]-ethyl}-ace-
tamide;
N-{2-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,-
4-tetrahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-2-[(2-cyano-ethyl)-ethyl-am-
ino]-ethyl}-acetamide;
N-{2-[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-qui-
nazolin-7-yl)-pyrrolidin-3-yl]-2-[(2-cyano-ethyl)-ethyl-amino]-ethyl}-acet-
amide;
3-{[1-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydr-
o-quinazolin-7-yl)-pyrrolidin-3-ylmethyl]-ethyl-amino}-propionitrile,
3-{[1-(1-Cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7--
yl)-pyrrolidin-3-ylmethyl]-ethyl-amino}-propionitrile;
3-({1-[1-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-qu-
inazolin-7-yl)-pyrrolidin-3-yl]-ethyl}-ethyl-amino)-propionitrile;
and
3-({1-[1-(1-Cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-
-7-yl)-pyrrolidin-3-yl]-ethyl}-ethyl-amino)-propionitrile.
16. The compound, or a pharmaceutically acceptable salt thereof, of
claim 1 selected from the group consisting of:
3-({1-[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-qui-
nazolin-7-yl)-pyrrolidin-3-yl]-ethyl}-methyl-amino)-propionitrile;
3-({1-[1-(1-Cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin--
7-yl)-pyrrolidin-3-yl]-ethyl}-methyl-amino)-propionitrile;
3-{[1-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quina-
zolin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-ethyl-amino}-propionitrile;
3-{[1-(1-Cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7--
yl)-3-methyl-pyrrolidin-3-ylmethyl]-ethyl-amino}-propionitrile;
3-{[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinaz-
olin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-ethyl-amino}-propionitrile;
3-{[1-(1-Cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-y-
l)-3-methyl-pyrrolidin-3-ylmethyl]-ethyl-amino}-propionitrile;
3-({1-[1-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-qu-
inazolin-7-yl)-pyrrolidin-3-yl]-cyclopropyl}-ethyl-amino)-propionitrile;
3-({1-[1-(1-Cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-
-7-yl)-pyrrolidin-3-yl]-cyclopropyl}-ethyl-amino)-propionitrile;
3-({1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-pyrrolidin-3-yl]-cyclopropyl}-ethyl-amino)-propioni-
trile;
3-({1-[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrah-
ydro-quinazolin-7-yl)-pyrrolidin-3-yl]-cyclopropyl}-ethyl-amino)-propionit-
rile;
N-{2-[1-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-pyrrolidin-3-yl]-2-[(2-cyano-ethyl)-ethyl-amino]-ethyl-
}-acetamide;
N-{2-[(2-Cyano-ethyl)-ethyl-amino]-2-[1-(1-cyclopropyl-8-methoxy-2,4-diox-
o-1,2,3,4-tetrahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-ethyl}-acetamide;
N-{2-[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quin-
azolin-7-yl)-pyrrolidin-3-yl]-2-[(2-cyano-ethyl)-ethyl-amino]-ethyl}-aceta-
mide;
N-{2-[(2-Cyano-ethyl)-ethyl-amino]-2-[1-(1-cyclopropyl-8-methyl-2,4-
-dioxo-1,2,3,4-tetrahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-ethyl}-acetami-
de;
3-{1-[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro--
quinazolin-7-yl)-azetidin-3-yl]-propylamino}-propionitrile;
3-{1-[1-(1-Cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-
-yl)-azetidin-3-yl]-propylamino}-propionitrile;
3-{[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinaz-
olin-7-yl)-3-methyl-azetidin-3-ylmethyl]-amino}-propionitrile;
3-{[1-(1-Cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-y-
l)-3-methyl-azetidin-3-ylmethyl]-amino}-propionitrile;
3-{1-[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quin-
azolin-7-yl)-azetidin-3-yl]-cyclopropylamino}-propionitrile;
3-{1-[1-(1-Cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-
-yl)-azetidin-3-yl]-cyclopropylamino}-propionitrile;
3-{[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinaz-
olin-7-yl)-3-ethyl-azetidin-3-ylmethyl]-amino}-propionitrile;
3-[1-(1-Cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-yl-
)-3-ethyl-azetidin-3-ylmethyl]-amino}-propionitrile=;
3-Amino-3-[1-(5-amino-8-fluoro-3-methyl-4,6-dioxo-2,3,5,6-tetrahydro-4H-1-
-oxa-3a,5-diaza-phenalen-9-yl)-pyrolidin-3-yl]-propionitrile;
3-Amino-3-[1-(8-fluoro-3-methyl-4,6-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,-
5-diaza-phenalen-9-yl)-pyrolidin-3-yl]-propionitrile;
3-Amino-3-[1-(3-amino-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-
-pyrido[2,3-d]pyrimidin-7-yl)-pyrrolidin-3-yl]-propionitrile;
3-Amino-3-[1-(1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-pyrido[-
2,3-d]pyrimidin-7-yl)-pyrrolidin-3-yl]-propionitrile;
3-Amino-3-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4--
tetrahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-propionitrile;
3-Amino-3-[1-(1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-pyrrolidin-3-yl]-propionitrile;
3-Amino-3-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-t-
etrahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-propionitrile;
3-Amino-3-[1-(1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydr-
o-quinazolin-7-yl)-pyrrolidin-3-yl]-propionitrile;
3-Amino-3-[1-(3-amino-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-
-quinazolin-7-yl)-pyrrolidin-3-yl]-propionitrile;
3-Amino-3-[1-(1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-quinazo-
lin-7-yl)-pyrrolidin-3-yl]-propionitrile;
3-Amino-3-[1-(3-amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydr-
o-quinazolin-7-yl)-pyrrolidin-3-yl]-propionitrile;
3-Amino-3-[1-(1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinaz-
olin-7-yl)-pyrrolidin-3-yl]-propionitrile;
3-Amino-3-[1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
-quinazolin-7-yl)-pyrrolidin-3-yl]-propionitrile;
3-Amino-3-[1-(1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazo-
lin-7-yl)-pyrrolidin-3-yl]-propionitrile;
3-Amino-3-[1-(3,5-diamino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-pyrrolidin-3-yl]-propionitrile;
3-Amino-3-[1-(5-amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydr-
o-quinazolin-7-yl)-pyrrolidin-3-yl]-propionitrile;
3-Amino-3-[1-(3,5-diamino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrah-
ydro-quinazolin-7-yl)-pyrrolidin-3-yl]-propionitrile;
3-Amino-3-[1-(5-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
-quinazolin-7-yl)-pyrrolidin-3-yl]-propionitrile;
3-Amino-3-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4--
tetrahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-propionitrile;
3-Amino-3-[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-propionitrile;
3-Amino-3-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-t-
etrahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-propionitrile;
3-Amino-3-[1-(1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydr-
o-quinazolin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-propionitrile; and
3-Amino-3-[1-(3-amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydr-
o-quinazolin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-propionitrile.
17. The compound, or a pharmaceutically acceptable salt thereof, of
claim 1 selected from the group consisting of:
3-Amino-3-[1-(1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinaz-
olin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-propionitrile;
3-Amino-3-[1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
-quinazolin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-propionitrile;
3-Amino-3-[1-(1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazo-
lin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-propionitrile;
3-Amino-3-[1-(3,5-diamino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-propionitrile;
3-Amino-3-[1-(5-amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydr-
o-quinazolin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-propionitrile;
3-Amino-3-[1-(3,5-diamino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrah-
ydro-quinazolin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-propionitrile;
3-Amino-3-[1-(5-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
-quinazolin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-propionitrile;
3-Amino-3-[1-(3-amino-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-
-quinazolin-7-yl)-pyrrolidin-3-yl]-propionitrile;
3-Amino-3-[1-(1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-quinazo-
lin-7-yl)-pyrrolidin-3-yl]-propionitrile;
3-[1-(3-Amino-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-quinazo-
lin-7-yl)-pyrrolidin-3-yl]-3-methylamino-propionitrile;
3-[1-(1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-yl-
)-pyrrolidin-3-yl]-3-methylamino-propionitrile;
3-[1-(5-Amino-8-fluoro-3-methyl-4,6-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,-
5-diaza-phenalen-9-yl)-pyrrolidin-3-yl]-3-methylamino-propionitrile;
3-[1-(8-Fluoro-3-methyl-4,6-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,5-diaza--
phenalen-9-yl)-pyrrolidin-3-yl]-3-methylamino-propionitrile;
3-[1-(3-Amino-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-pyrido[-
2,3-d]pyrimidin-7-yl)-pyrrolidin-3-yl]-3-methylamino-propionitrile;
3-[1-(1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-pyrido[2,3-d]py-
rimidin-7-yl)-pyrrolidin-3-yl]-3-methylamino-propionitrile;
3-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-pyrrolidin-3-yl]-3-methylamino-propionitrile;
3-[1-(1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quina-
zolin-7-yl)-pyrrolidin-3-yl]-3-methylamino-propionitrile;
3-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydr-
o-quinazolin-7-yl)-pyrrolidin-3-yl]-3-methylamino-propionitrile;
3-[1-(1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinaz-
olin-7-yl)-pyrrolidin-3-yl]-3-methylamino-propionitrile;
3-[1-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinaz-
olin-7-yl)-pyrrolidin-3-yl]-3-methylamino-propionitrile;
3-[1-(1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-y-
l)-pyrrolidin-3-yl]-3-methylamino-propionitrile;
3-[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazo-
lin-7-yl)-pyrrolidin-3-yl]-3-methylamino-propionitrile;
3-[1-(1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-yl-
)-pyrrolidin-3-yl]-3-methylamino-propionitrile;
3-[1-(3,5-Diamino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-qu-
inazolin-7-yl)-pyrrolidin-3-yl]-3-methylamino-propionitrile;
3-[1-(5-amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinaz-
olin-7-yl)-pyrolidin-3-yl]-3-methylamino-propionitrile;
3-[1-(3,5-Diamino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-qui-
nazolin-7-yl)-pyrrolidin-3-yl]-3-methylamino-propionitrile;
3-[1-(5-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazo-
lin-7-yl)-pyrrolidin-3-yl]-3-methylamino-propionitrile;
3-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-3-methylamino-propionitr-
ile;
3-[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro--
quinazolin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-3-dimethylamino-propionitri-
le;
3-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-3-methylamino-propion-
itrile;
3-[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydr-
o-quinazolin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-3-methylamino-propionitri-
le;
3-[1-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-qu-
inazolin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-3-methylamino-propionitrile;
3-[1-(1-Cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-y-
l)-pyrrolidin-3-yl]-2,2-dimethyl-3-methylamino-propionitrile;
3-[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazo-
lin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-3-methylamino-propionitrile;
3-[1-(1-Cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-yl-
)-pyrrolidin-3-yl]-2,2-dimethyl-3-methylamino-propionitrile;
3-[1-(3,5-Diamino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-qu-
inazolin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-3-methylamino-propionitrile;
3-[1-(5-amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinaz-
olin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-3-methylamino-propionitrile;
3-[1-(3,5-Diamino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-qui-
nazolin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-3-methylamino-propionitrile;
3-[1-(5-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazo-
lin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-3-methylamino-propionitrile;
3-[2-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-octahydro-cyclopenta[c]pyrrol-4-ylamino]-propionitrile-
;
3-[2-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quin-
azolin-7-yl)-octahydro-cyclopenta[c]pyrrol-4-ylamino]-propionitrile;
3-[2-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinaz-
olin-7-yl)-octahydro-cyclopenta[c]pyrrol-4-ylamino]-propionitrile;
3-[2-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quina-
zolin-7-yl)-octahydro-cyclopenta[c]pyrrol-4-ylamino]-propionitrile;
3-[2-(1-Cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-y-
l)-octahydro-cyclopenta[c]pyrrol-4-ylamino]-propionitrile; and
3-[2-(1-Cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-yl-
)-octahydro-cyclopenta[c]pyrrol-4-ylamino]-propionitrile.
18. A pharmaceutical formulation comprising a compound of formula
I, II, III, IV, V, or VI admixed with a pharmaceutically acceptable
diluent, carrier, or excipient.
19. A method of treating a bacterial infection in a mammal,
comprising administering to a mammal in need thereof an effective
amount of a compound of formula I, II, III, IV, V, or VI.
Description
FIELD OF THE INVENTION
[0001] The invention relates to compounds bearing a
aminoquinazolinedione core structure which exhibit antibacterial
activity, methods for their preparation, as well as
pharmaceutically acceptable compositions comprising such
compounds.
BACKGROUND OF THE INVENTION
[0002] Antibacterial resistance is a global clinical and public
health problem that has emerged with alarming rapidity in recent
years. Resistance is a problem in the community as well as in
health care settings, where transmission of bacteria is greatly
amplified. Because multiple drug resistance is a growing problem,
physicians are now confronted with infections for which there is no
effective therapy. The morbidity, mortality, and financial costs of
such infections pose an increasing burden for health care systems
worldwide. As a result, alternative and improved agents are needed
for the treatment of bacterial infections, particularly for the
treatment of infections caused by resistant strains of
bacteria.
SUMMARY OF THE INVENTION
[0003] These and other needs are met by the present invention,
which is directed to a compound of formula I: ##STR1## [0004] or a
pharmaceutically acceptable salt thereof, wherein: [0005] X is N or
C, provided that when X is N, R.sub.5 is absent at that position;
[0006] R.sub.1 is (C.sub.1-C.sub.6)alkyl, [0007]
halo(C.sub.1-C.sub.6)alkyl, [0008] (C.sub.3-C.sub.6)cycloalkyl,
[0009] halo(C.sub.3-C.sub.6)cycloalkyl [0010] aryl, and [0011]
heteroaryl; [0012] CH.sub.2(C.sub.3-C.sub.6)cycloalkyl; [0013]
R.sub.2 is H, [0014] NH.sub.2, ##STR2## [0015]
NH(C.sub.1-C.sub.6)alkyl, [0016] NH(C.sub.3-C.sub.6)cycloalkyl,
[0017] NH-aryl, [0018] NH-heteroaryl, [0019]
NHSO.sub.2--(C.sub.1-C.sub.6)alkyl, [0020] NHSO.sub.2-aryl, [0021]
NHSO.sub.2-heteroaryl, ##STR3## [0022] wherein g is an integer from
1 to 10, Q is O, NH, or is absent, and R.sub.2a and R.sub.2A ' are
each independently H or (C.sub.1-C.sub.6)alkyl, or taken together
with the carbons to which they are attached form a 3, 4, 5, or
6-membered substituted or unsubstituted ring, and R.sub.2b is
(C.sub.1-C.sub.6)alkyl, aryl, or heteroaryl, ##STR4## [0023]
wherein R.sub.2a and R.sub.2a'are as defined above, ##STR5## [0024]
wherein indicates the point of attachment, p is 0 or 1, and [0025]
R.sub.2c is H, [0026] (C.sub.1-C.sub.6)alkyl, [0027]
O(C.sub.1-C.sub.6)alkyl, [0028] (C.sub.3-C.sub.7)cycloalkyl, [0029]
aryl, [0030] heterocyclo, [0031] heteroaryl, or ##STR6## [0032]
wherein R.sub.2a, R.sub.2b, and Q, are as defined above, and h and
n are each independently integers from 0 to 10, and Y is OH,
OPO(OH).sub.2, OPO(O(C.sub.1-C.sub.6)).sub.2, or NR.sub.2dR.sub.2e,
wherein R.sub.2d and R.sub.2e are each independently H,
(C.sub.1-C.sub.6)alkyl, or (C.sub.3-C.sub.7)cycloalkyl, ##STR7##
[0033] wherein q is 0 or 1, R.sub.2f and R.sub.2f are each
independently H, (C.sub.1-C.sub.6)alkyl, aryl, or heteroaryl, or
taken together with the carbon to which they are attached form a 3,
4, 5, or 6 membered substituted or unsubstituted ring, and R.sub.2g
is [0034] (C.sub.1-C.sub.6)alkyl, [0035]
(C.sub.3-C.sub.7)cycloalkyl, [0036] aryl, or [0037] heterocyclo, or
[0038] heteroaryl; [0039] R.sub.3, R.sub.4, and R.sub.5 are each
independently H, [0040] halo, [0041] NH.sub.2, [0042]
(C.sub.1-C.sub.6)alkyl, [0043] halo(C.sub.1-C.sub.6)alkyl, [0044]
(C.sub.1-C.sub.6)alkoxy, or [0045] halo(C.sub.1-C.sub.6)alkoxy
[0046] nitrile; or [0047] R.sub.1 and R.sub.5 taken together with
the carbons to which they are attached form a substituted or
unsubstituted 5- or 6-membered substituted or unsubstituted ring
containing 0, 1, or 2 heteroatoms selected from O, S, SO, SO.sub.2,
or NR.sub.x, wherein R.sub.x is H or (C.sub.1-C.sub.6)alkyl; and
[0048] A is ##STR8## [0049] wherein z is 0, 1, or 2 and q is 0, 1,
2, or 3; [0050] R.sub.a and R.sub.b are each independently H,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
halo(C.sub.1-C.sub.6)alkyl, halo, or R.sub.a and R.sub.b taken
together with the carbon to which they are attached form C.dbd.O,
C.dbd.NO(C.sub.1-C.sub.6)alkyl, or a 3, 4, 5 or 6-membered
substituted or unsubstituted ring; [0051] R', R'', R''', and R''''
are each independently H, [0052] (C.sub.1-C.sub.6)alkyl, [0053]
--O(C.sub.1-C.sub.6)alkyl, [0054] halo(C.sub.1-C.sub.6)alkyl,
[0055] aryl, or [0056] heteroaryl; [0057] and B is ##STR9## [0058]
provided that when B is ##STR10## [0059] R' is not
--O(C.sub.1-C.sub.6)alkyl, and wherein indicates the point of
attachment; [0060] R.sub.c and R.sub.d are each independently H,
[0061] (C.sub.1-C.sub.6)alkylnitrile; ##STR11## [0062]
(C.sub.1-C.sub.6)alkyl, [0063] (C.sub.3-C.sub.6)cycloalkyl, [0064]
heteroaryl, [0065] SO.sub.2--(C.sub.1-C.sub.6)alkyl, [0066]
SO.sub.2-aryl, [0067] SO.sub.2-heteroaryl, ##STR12## [0068] wherein
g is an integer from 1 to 10, Q is as defined above, and R.sub.2a
and R.sub.2a' are each independently H or (C.sub.1-C.sub.6)alkyl,
or taken together with the carbons to which they are attached form
a 3, 4, 5, or 6-membered substituted or unsubstituted ring, and
R.sub.2b is (C.sub.1-C.sub.6)alkyl, aryl, or heteroaryl, ##STR13##
[0069] wherein R.sub.2a and R.sub.2a' are as defined above,
##STR14## [0070] wherein indicates the point of attachment, p is 0
or 1, and [0071] R.sub.2 is H, [0072] (C.sub.1-C.sub.6)alkyl,
[0073] O(C.sub.1-C.sub.6)alkyl, [0074] (C.sub.3-C.sub.7)cycloalkyl,
[0075] aryl, [0076] heterocyclo, [0077] heteroaryl, or ##STR15##
[0078] wherein R.sub.2a, R.sub.2b, and Q are as defined above, and
h and j are each independently integers from 0 to 10, and Y is OH,
OPO(OH).sub.2, OPO(O(C.sub.1-C.sub.6)).sub.2, or NR.sub.2dR.sub.2e,
wherein R.sub.2d and R.sub.2e are each independently H,
(C.sub.1-C.sub.6)alkyl, or (C.sub.3-C.sub.7)cycloalkyl, ##STR16##
[0079] wherein q is 0 or 1, R.sub.2f and R.sub.2f are each
independently H, (C.sub.1-C.sub.6)alkyl, aryl, or heteroaryl, or
taken together with the carbon to which they are attached form a 3,
4, 5, or 6 membered substituted or unsubstituted ring, and R.sub.2g
is [0080] (C.sub.1-C.sub.6)alkyl, [0081]
(C.sub.3-C.sub.7)cycloalkyl, [0082] aryl, or [0083] heterocyclo, or
[0084] heteroaryl; [0085] R.sub.e and R.sub.f are each
independently H, C.sub.1-C.sub.6 alkyl, haloalkyl, halo, or R.sub.e
and R.sub.f taken together with the carbon to which they are
attached form a 3, 4, 5 or 6-membered substituted or unsubstituted
ring; [0086] R.sub.g and R.sub.h are each independently H,
C.sub.1-C.sub.6 alkyl, haloalkyl, or taken together with the carbon
to which they are attached to form a 3, 4, 5 or 6-membered
substituted or unsubstituted ring; and [0087] R.sub.j and R.sub.k
are each independently H, (C.sub.1-C.sub.6)alkyl, haloalkyl,
(C.sub.1-C.sub.6)alkyl-NR.sub.cR.sub.d,
(C.sub.1-C.sub.6)alkyl-OR.sub.c, aryl, heteroaryl, heterocycle,
##STR17## [0088] wherein Z is O or NR.sub.c, or R.sub.j and R.sub.k
taken together with the carbon to which they are attached to form a
3, 4, 5 or 6-membered substituted or unsubstituted ring.
[0089] What is also provided is a compound of formula II: ##STR18##
[0090] or a pharmaceutically acceptable salt thereof, wherein:
[0091] X is N or C, provided that when X is N, R.sub.5 is absent at
that position; [0092] n is 0, 1, or 2; [0093] R.sub.1 is
(C.sub.1-C.sub.6)alkyl, [0094] halo(C.sub.1-C.sub.6)alkyl, [0095]
(C.sub.3-C.sub.6)cycloalkyl, [0096] halo(C.sub.3-C.sub.6)cycloalkyl
[0097] aryl, and [0098] heteroaryl; [0099]
CH.sub.2(C.sub.3-C.sub.6)cycloalkyl; [0100] R.sub.2 is H, [0101]
NH.sub.2, ##STR19## [0102] NH(C.sub.1-C.sub.6)alkyl, [0103]
NH(C.sub.3-C.sub.6)cycloalkyl, [0104] NH-aryl, [0105]
NH-heteroaryl, [0106] NHSO.sub.2--(C.sub.1-C.sub.6)alkyl, [0107]
NHSO.sub.2-aryl, [0108] NHSO.sub.2-heteroaryl, ##STR20## [0109]
wherein g is an integer from 1 to 10, Q is O, NH, or is absent, and
R.sub.2a and R.sub.2a' are each independently H or
(C.sub.1-C.sub.6)alkyl, or taken together with the carbons to which
they are attached form a 3, 4, 5, or 6-membered substituted or
unsubstituted ring, and R.sub.2b is (C.sub.1-C.sub.6)alkyl, aryl,
or heteroaryl, ##STR21## [0110] wherein R.sub.2a and R.sub.2a' are
as defined above, ##STR22## [0111] wherein indicates the point of
attachment, p is 0 or 1, and [0112] R.sub.2c is H, [0113]
(C.sub.1-C.sub.6)alkyl, [0114] O(C.sub.1-C.sub.6)alkyl, [0115]
(C.sub.3-C.sub.7)cycloalkyl, [0116] aryl, [0117] heterocyclo,
[0118] heteroaryl, or ##STR23## [0119] wherein R.sub.2a, R.sub.2b,
and Q, are as defined above, and h and n are each independently
integers from 0 to 10, and Y is OH, OPO(OH).sub.2,
OPO(O(C.sub.1-C.sub.6)).sub.2, or NR.sub.2dR.sub.2e, wherein
R.sub.2d and R.sub.2e are each independently H,
(C.sub.1-C.sub.6)alkyl, or (C.sub.3-C.sub.7)cycloalkyl, ##STR24##
[0120] wherein q is 0 or 1, R.sub.2f and R.sub.2f' are each
independently H, (C.sub.1-C.sub.6)alkyl, aryl, or heteroaryl, or
taken together with the carbon to which they are attached form a 3,
4, 5, or 6 membered substituted or unsubstituted ring, and R.sub.2g
is [0121] (C.sub.1-C.sub.6)alkyl, [0122]
(C.sub.3-C.sub.7)cycloalkyl, [0123] aryl, or [0124] heterocyclo, or
[0125] heteroaryl; [0126] R.sub.3, R.sub.4, and R.sub.5 are each
independently H, [0127] halo, [0128] NH.sub.2, [0129]
(C.sub.1-C.sub.6)alkyl, [0130] halo(C.sub.1-C.sub.6)alkyl, [0131]
(C.sub.1-C.sub.6)alkoxy, or [0132] halo(C.sub.1-C.sub.6)alkoxy
[0133] nitrile; or [0134] R.sub.1 and R.sub.5 taken together with
the carbons to which they are attached form a substituted or
unsubstituted 5- or 6-membered substituted or unsubstituted ring
containing 0, 1, or 2 heteroatoms selected from O, S, SO, SO.sub.2,
or NR.sub.x, wherein R.sub.x is H or (C.sub.1-C.sub.6)alkyl; and
[0135] z is 0, 1, or 2; [0136] R' is H, [0137]
(C.sub.1-C.sub.6)alkyl, [0138] halo(C.sub.1-C.sub.6)alkyl, [0139]
aryl, or [0140] heteroaryl; [0141] R.sub.a and R.sub.b are each
independently H, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
halo(C.sub.1-C.sub.6)alkyl, halo, or R.sub.a and R.sub.b taken
together with the carbon to which they are attached form C.dbd.O,
C.dbd.NO(C.sub.1-C.sub.6)alkyl, or a 3, 4, 5 or 6-membered
substituted or unsubstituted ring; [0142] R.sub.c is H, [0143]
(C.sub.1-C.sub.6)alkylnitrile; ##STR25## [0144]
(C.sub.1-C.sub.6)alkyl, [0145] (C.sub.3-C.sub.6)cycloalkyl, [0146]
heteroaryl, [0147] SO.sub.2--(C.sub.1-C.sub.6)alkyl, [0148]
SO.sub.2-aryl, [0149] SO.sub.2-heteroaryl, ##STR26## [0150] wherein
g is an integer from 1 to 10, Q is as defined above, and R.sub.2a
and R.sub.2a', are each independently H or (C.sub.1-C.sub.6)alkyl,
or taken together with the carbons to which they are attached form
a 3, 4, 5, or 6-membered substituted or unsubstituted ring, and
R.sub.2b is (C.sub.1-C.sub.6)alkyl, aryl, or heteroaryl, ##STR27##
[0151] wherein R.sub.2a and R.sub.2a' are as defined above,
##STR28## [0152] wherein indicates the point of attachment, p is 0
or 1, and [0153] R.sub.2 is H, [0154] (C.sub.1-C.sub.6)alkyl,
[0155] O(C.sub.1-C.sub.6)alkyl, [0156] (C.sub.3-C.sub.7)cycloalkyl,
[0157] aryl, [0158] heterocyclo, [0159] heteroaryl, or ##STR29##
[0160] wherein R.sub.2a, R.sub.2b, and Q are as defined above, and
h and j are each independently integers from 0 to 10, and Y is OH,
OPO(OH).sub.2, OPO(O(C.sub.1-C.sub.6)).sub.2, or NR.sub.2dR.sub.2e,
wherein R.sub.2d and R.sub.2e are each independently H,
(C.sub.1-C.sub.6)alkyl, or (C.sub.3-C.sub.7)cycloalkyl, ##STR30##
[0161] wherein q is 0 or 1, R.sub.2f and R.sub.2f' are each
independently H, (C.sub.1-C.sub.6)alkyl, aryl, or heteroaryl, or
taken together with the carbon to which they are attached form a 3,
4, 5, or 6 membered substituted or unsubstituted ring, and R.sub.2g
is [0162] (C.sub.1-C.sub.6)alkyl, [0163]
(C.sub.3-C.sub.7)cycloalkyl, [0164] aryl, or [0165] heterocyclo, or
[0166] heteroaryl; [0167] R.sub.e and R.sub.f are each
independently H, C.sub.1-C.sub.6 alkyl, haloalkyl, halo, or R.sub.e
and R.sub.f taken together with the carbon to which they are
attached form a 3, 4, 5 or 6-membered substituted or unsubstituted
ring; and [0168] R.sub.g and R.sub.h are each independently H,
C.sub.1-C.sub.6 alkyl, haloalkyl, or taken together with the carbon
to which they are attached to form a 3, 4, 5 or 6-membered
substituted or unsubstituted ring.
[0169] What is also provided is a compound which is ##STR31##
[0170]
3-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-pyrrolidin-3-ylamino]-propionitrile; ##STR32##
[0171]
3-[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-pyrrolidin-3-ylamino]-propionitrile; ##STR33##
[0172]
3-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-t-
etrahydro-quinazolin-7-yl)-pyrrolidin-3-ylamino]-propionitrile;
##STR34## [0173]
3-[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinaz-
olin-7-yl)-pyrrolidin-3-ylamino]-propionitrile; ##STR35## [0174]
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahy-
dro-quinazolin-7-yl)-pyrrolidin-3-yl]-methyl-amino}-propionitrile;
##STR36## [0175]
3-{[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quin-
azolin-7-yl)-pyrrolidin-3-yl]-methyl-amino}-propionitrile;
##STR37## [0176]
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4--
tetrahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-methyl-amino}-propionitrile;
or ##STR38## [0177]
3-{[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quina-
zolin-7-yl)-pyrrolidin-3-yl]-methyl-amino}-propionitrile.
[0178] What is also provided is a compound of formula III:
##STR39## [0179] or a pharmaceutically acceptable salt thereof,
wherein: [0180] X is N or C, provided that when X is N, R.sub.5 is
absent at that position; [0181] n is 0, 1, or 2; [0182] R.sub.1 is
(C.sub.1-C.sub.6)alkyl, [0183] halo(C.sub.1-C.sub.6)alkyl, [0184]
(C.sub.3-C.sub.6)cycloalkyl, [0185] halo(C.sub.3-C.sub.6)cycloalkyl
[0186] aryl, and [0187] heteroaryl; [0188]
CH.sub.2(C.sub.3-C.sub.6)Cycloalkyl; [0189] R.sub.2 is H, [0190]
NH.sub.2, ##STR40## [0191] NH(C.sub.1-C.sub.6)alkyl, [0192]
NH(C.sub.3-C.sub.6)cycloalkyl, [0193] NH-aryl, [0194]
NH-heteroaryl, [0195] NHSO.sub.2--(C.sub.1-C.sub.6)alkyl, [0196]
NHSO.sub.2-aryl, [0197] NHSO.sub.2-heteroaryl, ##STR41## [0198]
wherein g is an integer from 1 to 10, Q is O, NH, or is absent, and
R.sub.2a and R.sub.2a' are each independently H or
(C.sub.1-C.sub.6)alkyl, or taken together with the carbons to which
they are attached form a 3, 4, 5, or 6-membered substituted or
unsubstituted ring, and R.sub.2b is (C.sub.1-C.sub.6)alkyl, aryl,
or heteroaryl, ##STR42## [0199] wherein R.sub.2a and R.sub.2a' are
as defined above, ##STR43## [0200] wherein indicates the point of
attachment, p is 0 or 1, and [0201] R.sub.2c is H, [0202]
(C.sub.1-C.sub.6)alkyl, [0203] O(C.sub.1-C.sub.6)alkyl, [0204]
(C.sub.3-C.sub.7)cycloalkyl, [0205] aryl, [0206] heterocyclo,
[0207] heteroaryl, or ##STR44## [0208] wherein R.sub.2, R.sub.2b,
and Q, are as defined above, and h and n are each independently
integers from 0 to 10, and Y is OH, OPO(OH).sub.2,
OPO(O(C.sub.1-C.sub.6)).sub.2, or NR.sub.2dR.sub.2e, wherein
R.sub.2d and R.sub.2e are each independently H,
(C.sub.1-C.sub.6)alkyl, or (C.sub.3-C.sub.7)cycloalkyl, ##STR45##
[0209] wherein q is 0 or 1, R.sub.2f ' and R.sub.2f are each
independently H, (C.sub.1-C.sub.6)alkyl, aryl, or heteroaryl, or
taken together with the carbon to which they are attached form a 3,
4, 5, or 6 membered substituted or unsubstituted ring, and R.sub.2g
is [0210] (C.sub.1-C.sub.6)alkyl, [0211]
(C.sub.3-C.sub.7)cycloalkyl, [0212] aryl, or [0213] heterocyclo, or
[0214] heteroaryl; [0215] R.sub.3, R.sub.4, and R.sub.5 are each
independently H, [0216] halo, [0217] NH.sub.2, [0218]
(C.sub.1-C.sub.6)alkyl, [0219] halo(C.sub.1-C.sub.6)alkyl, [0220]
(C.sub.1-C.sub.6)alkoxy, or [0221] halo(C.sub.1-C.sub.6)alkoxy
[0222] nitrile; or [0223] R.sub.1 and R.sub.5 taken together with
the carbons to which they are attached form a substituted or
unsubstituted 5- or 6-membered substituted or unsubstituted ring
containing 0, 1, or 2 heteroatoms selected from O, S, SO, SO.sub.2,
or NR.sub.x, wherein R.sub.x is H or (C.sub.1-C.sub.6)alkyl; and
[0224] z is 0, 1, or 2; [0225] R' is H, [0226]
(C.sub.1-C.sub.6)alkyl, [0227] --O(C.sub.1-C.sub.6)alkyl, [0228]
halo(C.sub.1-C.sub.6)alkyl, [0229] aryl, or [0230] heteroaryl;
[0231] R.sub.a and R.sub.b are each independently H,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
halo(C.sub.1-C.sub.6)alkyl, halo, or R.sub.a and R.sub.b taken
together with the carbon to which they are attached form C.dbd.O,
C.dbd.NO(C.sub.1-C.sub.6)alkyl, or a 3, 4, 5 or 6-membered
substituted or unsubstituted ring; [0232] R.sub.c is H, [0233]
(C.sub.1-C.sub.6)alkylnitrile; ##STR46## [0234]
(C.sub.1-C.sub.6)alkyl, [0235] (C.sub.3-C.sub.6)cycloalkyl, [0236]
heteroaryl, [0237] SO.sub.2--(C.sub.1-C.sub.6)alkyl, [0238]
SO.sub.2-aryl, [0239] SO.sub.2-heteroaryl, ##STR47## [0240] wherein
g is an integer from 1 to 10, Q is as defined above, and R.sub.2a
and R.sub.2a are each independently H or (C.sub.1-C.sub.6)alkyl, or
taken together with the carbons to which they are attached form a
3, 4, 5, or 6-membered substituted or unsubstituted ring, and
R.sub.2b is (C.sub.1-C.sub.6)alkyl, aryl, or heteroaryl, ##STR48##
[0241] wherein R.sub.2a and R.sub.2a' are as defined above,
##STR49## [0242] wherein indicates the point of attachment, p is 0
or 1, and [0243] R.sub.2c is H, [0244] (C.sub.1-C.sub.6)alkyl,
[0245] O(C.sub.1-C.sub.6)alkyl, [0246] (C.sub.3-C.sub.7)cycloalkyl,
[0247] aryl, [0248] heterocyclo, [0249] heteroaryl, or ##STR50##
[0250] wherein R.sub.2a, R.sub.2b, and Q are as defined above, and
h and j are each independently integers from 0 to 10, and Y is OH,
OPO(OH).sub.2, OPO(O(C.sub.1-C.sub.6)).sub.2, or NR.sub.2dR.sub.2e,
wherein R.sub.2d and R.sub.2e are each independently H,
(C.sub.1-C.sub.6)alkyl, or (C.sub.3-C.sub.7)cycloalkyl, ##STR51##
[0251] wherein q is 0 or 1, R.sub.2f and R.sub.2f' are each
independently H, (C.sub.1-C.sub.6)alkyl, aryl, or heteroaryl, or
taken together with the carbon to which they are attached form a 3,
4, 5, or 6 membered substituted or unsubstituted ring, and R.sub.2g
is [0252] (C.sub.1-C.sub.6)alkyl, [0253]
(C.sub.3-C.sub.7)cycloalkyl, [0254] aryl, or [0255] heterocyclo, or
[0256] heteroaryl; [0257] R.sub.e and R.sub.f are each
independently H, C.sub.1-C.sub.6 alkyl, haloalkyl, halo, or R.sub.e
and R.sub.f taken together with the carbon to which they are
attached form a 3, 4, 5 or 6-membered substituted or unsubstituted
ring; [0258] R.sub.g and R.sub.h are each independently H,
C.sub.1-C.sub.6 alkyl, haloalkyl, or taken together with the carbon
to which they are attached to form a 3, 4, 5 or 6-membered
substituted or unsubstituted ring; and [0259] R.sub.j and R.sub.k
are each independently H, (C.sub.1-C.sub.6)alkyl, haloalkyl,
(C.sub.1-C.sub.6)alkyl-NR.sub.cR.sub.d,
(C.sub.1-C.sub.6)alkyl-OR.sub.c, aryl, heteroaryl, heterocycle,
##STR52## [0260] wherein Z is O or NR.sub.c, or R.sub.j and R.sub.k
taken together with the carbon to which they are attached to form a
3, 4, 5 or 6-membered substituted or unsubstituted ring.
[0261] What is also provided is a compound which is ##STR53##
[0262]
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahy-
dro-quinazolin-7-yl)-pyrrolidin-3-ylmethyl]-amino}-propionitrile;
##STR54## [0263]
3-{[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quin-
azolin-7-yl)-pyrrolidin-3-ylmethyl]-amino}-propionitrile; ##STR55##
[0264]
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4--
tetrahydro-quinazolin-7-yl)-pyrrolidin-3-ylmethyl]-amino}-propionitrile;
##STR56## [0265]
3-{[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quina-
zolin-7-yl)-pyrrolidin-3-ylmethyl]-amino}-propionitrile; ##STR57##
[0266]
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-
-tetrahydro-quinazolin-7-yl)-pyrrolidin-3-ylmethyl]-methyl-amino}-propioni-
trile; ##STR58## [0267]
3-{[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quin-
azolin-7-yl)-pyrrolidin-3-ylmethyl]-methyl-amino}-propionitrile;
##STR59## [0268]
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-pyrrolidin-3-ylmethyl]-methyl-amino}-propionitrile;
##STR60## [0269]
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-pyrrolidin-3-ylmethyl]-methyl-amino}-propionitrile;
##STR61## [0270]
3-{1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-pyrrolidin-3-yl]-ethylamino}-propionitrile;
##STR62## [0271]
3-{1-[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-qu-
inazolin-7-yl)-pyrrolidin-3-yl]-ethylamino}-propionitrile;
##STR63## [0272]
3-{1-[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrah-
ydro-quinazolin-7-yl)-pyrrolidin-3-yl]-ethylamino}-propionitrile;
##STR64## [0273]
3-({1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetr-
ahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-ethyl}-methyl-amino)-propionitril-
e; ##STR65## [0274]
3-({1-[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-q-
uinazolin-7-yl)-pyrrolidin-3-yl]-ethyl}-methyl-amino)-propionitrile;
##STR66## [0275]
3-({1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-pyrrolidin-3-yl]-ethyl}-methyl-amino)-propionitrile-
; ##STR67## [0276]
3-({1-[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-qu-
inazolin-7-yl)-pyrrolidin-3-yl]-ethyl}-methyl-amino)-propionitrile;
##STR68## [0277]
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahy-
dro-quinazolin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-amino}-propionitrile;
##STR69## [0278]
3-{[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quin-
azolin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-amino}-propionitrile;
##STR70## [0279]
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-amino}-propionitrile;
##STR71## [0280]
3-{[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quina-
zolin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-amino}-propionitrile;
##STR72## [0281]
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahy-
dro-quinazolin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-methyl-amino}-propion-
itrile; ##STR73## [0282]
3-{[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quin-
azolin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-methyl-amino}-propionitrile;
##STR74## [0283]
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-methyl-amino}-propioni-
trile; ##STR75## [0284]
3-{[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quina-
zolin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-methyl-amino}-propionitrile;
##STR76## [0285]
3-{1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-pyrrolidin-3-yl]-cyclopropylamino}-propionitrile;
##STR77## [0286]
3-{1-[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-qu-
inazolin-7-yl)-pyrrolidin-3-yl]-cyclopropylamino}-propionitrile;
##STR78## [0287]
3-{1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrah-
ydro-quinazolin-7-yl)-pyrrolidin-3-yl]-cyclopropylamino}-propionitrile;
##STR79## [0288]
3-{1-[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-qui-
nazolin-7-yl)-pyrrolidin-3-yl]-cyclopropylamino}-propionitrile;
##STR80## [0289]
3-({1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetr-
ahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-cyclopropyl}-methyl-amino)-propio-
nitrile; ##STR81## [0290]
3-({1-[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-q-
uinazolin-7-yl)-pyrrolidin-3-yl]-cyclopropyl}-methyl-amino)-propionitrile;
##STR82## [0291]
3-({1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-pyrrolidin-3-yl]-cyclopropyl}-methyl-amino)-propion-
itrile; ##STR83## [0292]
3-({1-[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-qu-
inazolin-7-yl)-pyrrolidin-3-yl]-cyclopropyl}-methyl-amino)-propionitrile;
##STR84## [0293]
N-[2-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-pyrrolidin-3-yl]-2-(2-cyano-ethylamino)-ethyl]-acet-
amide; ##STR85## [0294]
N-[2-[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-qu-
inazolin-7-yl)-pyrrolidin-3-yl]-2-(2-cyano-ethylamino)-ethyl]-acetamide;
##STR86## [0295]
N-[2-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrah-
ydro-quinazolin-7-yl)-pyrrolidin-3-yl]-2-(2-cyano-ethylamino)-ethyl]-aceta-
mide; ##STR87## [0296]
N-[2-[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-qui-
nazolin-7-yl)-pyrrolidin-3-yl]-2-(2-cyano-ethylamino)-ethyl]-acetamide;
##STR88## [0297]
N-{2-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-pyrrolidin-3-yl]-2-[(2-cyano-ethyl)-methyl-amino]-e-
thyl}-acetamide; ##STR89## [0298]
N-{2-[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-qu-
inazolin-7-yl)-pyrrolidin-3-yl]-2-[(2-cyano-ethyl)-methyl-amino]-ethyl}-ac-
etamide; ##STR90## [0299]
N-{2-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrah-
ydro-quinazolin-7-yl)-pyrrolidin-3-yl]-2-[(2-cyano-ethyl)-methyl-amino]-et-
hyl}-acetamide; ##STR91## [0300]
N-{2-[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-qui-
nazolin-7-yl)-pyrrolidin-3-yl]-2-[(2-cyano-ethyl)-methyl-amino]-ethyl}-ace-
tamide; ##STR92## [0301]
3-{[1-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quina-
zolin-7-yl)-pyrrolidin-3-ylmethyl]-amino}-propionitrile; ##STR93##
[0302]
3-{[1-(1-Cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quina-
zolin-7-yl)-pyrrolidin-3-ylmethyl]-amino}-propionitrile; ##STR94##
[0303]
3-{[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydr-
o-quinazolin-7-yl)-pyrrolidin-3-ylmethyl]-amino}-propionitrile;
##STR95## [0304]
3-{[1-(1-Cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-y-
l)-pyrrolidin-3-ylmethyl]-amino}-propionitrile; ##STR96## [0305]
3-{[1-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quina-
zolin-7-yl)-pyrrolidin-3-ylmethyl]-methyl-amino}-propionitrile;
##STR97## [0306]
3-{[1-(1-Cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7--
yl)-pyrrolidin-3-ylmethyl]-methyl-amino}-propionitrile; ##STR98##
[0307]
3-{[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydr-
o-quinazolin-7-yl)-pyrrolidin-3-ylmethyl]-methyl-amino}-propionitrile;
##STR99## [0308]
3-{[1-(1-Cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-y-
l)-pyrrolidin-3-ylmethyl]-methyl-amino}-propionitrile; ##STR100##
[0309]
3-{1-[1-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrah-
ydro-quinazolin-7-yl)-pyrrolidin-3-yl]-ethylamino}-propionitrile;
##STR101## [0310]
3-{1-[1-(1-(1-Cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinazol-
in-7-yl)-pyrrolidin-3-yl]-ethylamino}-propionitrile; ##STR102##
[0311]
3-{1-[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quin-
azolin-7-yl)-pyrrolidin-3-yl]-ethylamino}-propionitrile; ##STR103##
[0312]
3-{1-[1-(1-Cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quin-
azolin-7-yl)-pyrrolidin-3-yl]-ethylamino}-propionitrile; ##STR104##
[0313]
3-({1-[1-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-pyrrolidin-3-yl]-ethyl}-methyl-amino)-propionitrile-
; ##STR105## [0314]
3-({1-[1-(1-Cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-
-7-yl)-pyrrolidin-3-yl]-ethyl}-methyl-amino)-propionitrile;
##STR106## [0315]
3-({1-[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrah-
ydro-quinazolin-7-yl)-pyrrolidin-3-yl]-ethyl}-methyl-amino)-propionitrile;
##STR107## [0316]
3-({1-[1-(1-Cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin--
7-yl)-pyrrolidin-3-yl]-ethyl}-methyl-amino)-propionitrile;
##STR108## [0317]
3-{[1-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-amino}-propionitrile;
##STR109## [0318]
3-{[1-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quina-
zolin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl-amino}-propionitrile;
##STR110## [0319]
3-{[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinaz-
olin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-amino}-propionitrile;
##STR111## [0320]
3-{[1-(1-Cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-y-
l)-3-methyl-pyrrolidin-3-ylmethyl]-amino}-propionitrile; ##STR112##
[0321]
3-{[1-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-methyl-amino}-propioni-
trile; ##STR113## [0322]
3-{[1-(1-Cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7--
yl)-3-methyl-pyrrolidin-3-ylmethyl]-methyl-amino}-propionitrile;
##STR114## [0323]
3-{[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinaz-
olin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-methyl-amino]-propionitrile;
##STR115## [0324]
3-{[1-(1-Cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-y-
l)-3-methyl-pyrrolidin-3-ylmethyl]-methyl-amino}-propionitrile;
##STR116## [0325]
3-{1-[1-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-qui-
nazolin-7-yl)-pyrrolidin-3-yl]-cyclopropylamino}-propionitrile;
##STR117## [0326]
3-(1-[1-(1-Cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin--
7-yl)-pyrrolidin-3-yl]-cyclopropylamino}-propionitrile; ##STR118##
[0327]
3-{1-[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahy-
dro-quinazolin-7-yl)-pyrrolidin-3-yl]-cyclopropylamino}-propionitrile;
##STR119## [0328]
3-{1-[1-(1-Cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-
-yl)-pyrrolidin-3-yl]-cyclopropylamino}-propionitrile; ##STR120##
[0329]
3-({1-[1-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-pyrrolidin-3-yl]-cyclopropyl}-methyl-amino)-propion-
itrile; ##STR121## [0330]
3-({1-[1-(1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-
-7-yl)-pyrrolidin-3-yl]-cyclopropyl}-methyl-amino)-propionitrile;
##STR122## [0331]
3-({1-[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-qui-
nazolin-7-yl)-pyrrolidin-3-yl]-cyclopropyl}-methyl-amino)-propionitrile;
##STR123## [0332]
3-({1-[1-(1-Cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin--
7-yl)-pyrrolidin-3-yl]-cyclopropyl}-methyl-amino)-propionitrile;
##STR124## [0333]
N-[2-[1-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-qui-
nazolin-7-yl)-pyrrolidin-3-yl]-2-(2-cyano-ethylamino)-ethyl]-acetamide;
##STR125## [0334]
N-[2-[1-(1-Cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin--
7-yl)-pyrrolidin-3-yl]-2-(2-cyano-ethylamino)-ethyl]-acetamide;
##STR126## [0335]
N-[2-[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quin-
azolin-7-yl)-pyrrolidin-3-yl]-2-(2-cyano-ethylamino)-ethyl]-acetamide;
##STR127## [0336]
N-[2-[1-(1-Cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-
-yl)-pyrrolidin-3-yl]-2-(2-cyano-ethylamino)-ethyl]-acetamide;
##STR128## [0337]
N-{2-[1-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-qui-
nazolin-7-yl)-pyrrolidin-3-yl]-2-[(2-cyano-ethyl)-methyl-amino]-ethyl}-ace-
tamide; ##STR129## [0338]
N-{2-[1-(1-Cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin--
7-yl)-pyrrolidin-3-yl]-2-[(2-cyano-ethyl)-methyl-amino]-ethyl}-acetamide;
##STR130## [0339]
N-{2-[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quin-
azolin-7-yl)-pyrrolidin-3-yl]-2-[(2-cyano-ethyl)-methyl-amino]-ethyl}-acet-
amide; ##STR131## [0340]
N-{2-[1-(1-Cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-
-yl)-pyrrolidin-3-yl]-2-[(2-cyano-ethyl)-methyl-amino]-ethyl}-acetamide;
##STR132## [0341]
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahy-
dro-quinazolin-7-yl)-pyrrolidin-3-ylmethyl]-amino}-butyronitrile;
##STR133## [0342]
3-{[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quin-
azolin-7-yl)-pyrrolidin-3-ylmethyl]-amino}-butyronitrile;
##STR134## [0343]
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4--
tetrahydro-quinazolin-7-yl)-pyrrolidin-3-ylmethyl]-amino}-butyronitrile;
##STR135## [0344]
3-{[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quina-
zolin-7-yl)-pyrrolidin-3-ylmethyl]-amino}-butyronitrile; ##STR136##
[0345]
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-
-tetrahydro-quinazolin-7-yl)-pyrrolidin-3-ylmethyl]-methyl-amino}-butyroni-
trile; ##STR137## [0346]
3-{[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quin-
azolin-7-yl)-pyrrolidin-3-ylmethyl]-methyl-amino}-butyronitrile;
##STR138## [0347]
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-pyrrolidin-3-ylmethyl]-methyl-amino}-butyronitrile;
##STR139## [0348]
3-{[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quina-
zolin-7-yl)-pyrrolidin-3-ylmethyl]-methyl-amino}-butyronitrile;
##STR140## [0349]
3-[5-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-5-aza-spiro[2.4]hept-1-ylamino]-propionitrile;
##STR141## [0350]
3-[5-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quina-
zolin-7-yl)-5-aza-spiro[2.4]hept-1-ylamino]-propionitrile;
##STR142## [0351]
3-[5-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-t-
etrahydro-quinazolin-7-yl)-5-aza-spiro[2.4]hept-1-ylamino]-propionitrile;
##STR143## [0352]
3-[5-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinaz-
olin-7-yl)-5-aza-spiro[2.4]hept-1-ylamino]-propionitrile;
##STR144## [0353]
3-{1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3-
,4-tetrahydro-quinazolin-7-yl)-azetidin-3-yl]-propylamino}-propionitrile;
##STR145## [0354]
3-{1-[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-qu-
inazolin-7-yl)-azetidin-3-yl]-propylamino}-propionitrile;
##STR146## [0355]
3-{1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrah-
ydro-quinazolin-7-yl)-azetidin-3-yl]-propylamino}-propionitrile;
##STR147## [0356]
3-{1-[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-qui-
nazolin-7-yl)-azetidin-3-yl]-propylamino}-propionitrile; ##STR148##
[0357]
3-({1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,-
3,4-tetrahydro-quinazolin-7-yl)-azetidin-3-yl]-propyl}-methyl-amino)-propi-
onitrile; ##STR149## [0358]
3-({1-[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-q-
uinazolin-7-yl)-azetidin-3-yl]-propyl}-methyl-amino)-propionitrile;
##STR150## [0359]
3-({1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-azetidin-3-yl]-propyl}-methyl-amino)-propionitrile;
##STR151## [0360]
3-({1-[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-qu-
inazolin-7-yl)-azetidin-3-yl]-propyl}-methyl-amino)-propionitrile;
##STR152## [0361]
3-{1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-azetidin-3-yl]-cyclopropylamino}-propionitrile;
##STR153## [0362]
3-{1-[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-qu-
inazolin-7-yl)-azetidin-3-yl]-cyclopropylamino}-propionitrile;
##STR154## [0363]
3-{1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrah-
ydro-quinazolin-7-yl)-azetidin-3-yl]-cyclopropylamino}-propionitrile;
##STR155## [0364]
3-{1-[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-qui-
nazolin-7-yl)-azetidin-3-yl]-cyclopropylamino}-propionitrile;
##STR156## [0365]
3-({1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2-
,3,4-tetrahydro-quinazolin-7-yl)-azetidin-3-yl]-cyclopropyl}-methyl-amino)-
-propionitrile; ##STR157## [0366]
3-({1-[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-q-
uinazolin-7-yl)-azetidin-3-yl]-cyclopropyl}-methyl-amino)-propionitrile;
##STR158## [0367]
3-({1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-azetidin-3-yl]-cyclopropyl}-methyl-amino)-propionit-
rile; ##STR159## [0368]
3-({1-[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-qu-
inazolin-7-yl)-azetidin-3-yl]-cyclopropyl)-methyl-amino)-propionitrile;
##STR160## [0369]
3-({1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetr-
ahydro-quinazolin-7-yl)-azetidin-3-yl]-cyclopropyl}-ethyl-amino)-propionit-
rile; ##STR161## [0370]
3-({1-[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-q-
uinazolin-7-yl)-azetidin-3-yl]-cyclopropyl}-ethyl-amino)-propionitrile;
##STR162## [0371]
3-({1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-azetidin-3-yl]-cyclopropyl}-ethyl-amino)-propionitr-
ile; ##STR163## [0372]
3-({1-[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-qu-
inazolin-7-yl)-azetidin-3-yl]-cyclopropyl}-ethyl-amino)-propionitrile;
##STR164## [0373]
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahy-
dro-quinazolin-7-yl)-pyrrolidin-3-ylmethyl]-ethyl-amino}-propionitrile;
##STR165## [0374]
3-{[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quin-
azolin-7-yl)-pyrrolidin-3-ylmethyl]-ethyl-amino}-propionitrile;
##STR166## [0375]
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-pyrrolidin-3-ylmethyl]-ethyl-amino}-propionitrile;
##STR167## [0376]
3-{[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quina-
zolin-7-yl)-pyrrolidin-3-ylmethyl]-ethyl-amino}-propionitrile;
##STR168## [0377]
3-({1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetr-
ahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-ethyl}-ethyl-amino)-propionitrile-
; ##STR169## [0378]
3-({1-[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-q-
uinazolin-7-yl)-pyrrolidin-3-yl]-ethyl}-ethyl-amino)-propionitrile;
##STR170## [0379]
3-({1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-pyrrolidin-3-yl]-ethyl}-ethyl-amino)-propionitrile;
##STR171## [0380]
3-({1-[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-qu-
inazolin-7-yl)-pyrrolidin-3-yl]-ethyl}-ethyl-amino)-propionitrile;
##STR172## [0381]
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahy-
dro-quinazolin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-ethyl-amino}-propioni-
trile; ##STR173## [0382]
3-{[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quin-
azolin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-ethyl-amino}-propionitrile;
##STR174## [0383]
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-ethyl-amino}-propionit-
rile; ##STR175## [0384]
3-{[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quina-
zolin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-ethyl-amino}-propionitrile;
##STR176## [0385]
3-({1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetr-
ahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-cyclopropyl}-ethyl-amino)-propion-
itrile; ##STR177## [0386]
3-({1-[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-q-
uinazolin-7-yl)-pyrrolidin-3-yl]-cyclopropyl}-ethyl-amino)-propionitrile;
##STR178## [0387]
3-({1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-pyrrolidin-3-yl]-cyclopropyl}-ethyl-amino)-propioni-
trile; ##STR179## [0388]
3-({1-[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-qu-
inazolin-7-yl)-pyrrolidin-3-yl]-cyclopropyl}-ethyl-amino)-propionitrile;
##STR180## [0389]
N-{2-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-pyrrolidin-3-yl]-2-[(2-cyano-ethyl)-ethyl-amino]-et-
hyl}-acetamide; ##STR181## [0390]
N-{2-[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-qu-
inazolin-7-yl)-pyrrolidin-3-yl]-2-[(2-cyano-ethyl)-ethyl-amino]-ethyl}-ace-
tamide; ##STR182## [0391]
N-{2-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrah-
ydro-quinazolin-7-yl)-pyrrolidin-3-yl]-2-[(2-cyano-ethyl)-ethyl-amino]-eth-
yl}-acetamide; ##STR183## [0392]
N-{2-[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-qui-
nazolin-7-yl)-pyrrolidin-3-yl]-2-[(2-cyano-ethyl)-ethyl-amino]-ethyl}-acet-
amide; ##STR184## [0393]
3-{[1-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quina-
zolin-7-yl)-pyrrolidin-3-ylmethyl]-ethyl-amino}-propionitrile;
##STR185## [0394]
3-{[1-(1-Cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7--
yl)-pyrrolidin-3-ylmethyl]-ethyl-amino}-propionitrile; ##STR186##
[0395]
3-({1-[1-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-pyrrolidin-3-yl]-ethyl}-ethyl-amino)-propionitrile;
##STR187## [0396]
3-({1-[1-(1-Cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-
-7-yl)-pyrrolidin-3-yl]-ethyl}-ethyl-amino)-propionitrile;
##STR188## [0397]
3-({1-[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrah-
ydro-quinazolin-7-yl)-pyrrolidin-3-yl]-ethyl}-ethyl-amino)-propionitrile;
##STR189## [0398]
3-({1-[1-(1-Cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin--
7-yl)-pyrrolidin-3-yl]-ethyl}-ethyl-amino)-propionitrile;
##STR190## [0399]
3-{[1-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-ethyl-amino}-propionit-
rile; ##STR191## [0400]
3-{[1-(1-Cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7--
yl)-3-methyl-pyrrolidin-3-ylmethyl]-ethyl-amino}-propionitrile;
##STR192## [0401]
3-{[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinaz-
olin-7-yl)-3-methyl-pyrrolidin-3-ylmethyl]-ethyl-amino}-propionitrile;
##STR193## [0402]
3-{[1-(1-Cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-y-
l)-3-methyl-pyrrolidin-3-ylmethyl]-ethyl-amino}-propionitrile;
##STR194## [0403]
3-({1-[1-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-qu-
inazolin-7-yl)-pyrrolidin-3-yl]-cyclopropyl}-ethyl-amino)-propionitrile;
##STR195## [0404]
3-({1-[1-(1-Cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-
-7-yl)-pyrrolidin-3-yl]-cyclopropyl}-ethyl-amino)-propionitrile;
##STR196## [0405]
3-({1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-pyrrolidin-3-yl]-cyclopropyl}-ethyl-amino)-propioni-
trile; ##STR197## [0406]
3-({1-[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-qu-
inazolin-7-yl)-pyrrolidin-3-yl]-cyclopropyl}-ethyl-amino)-propionitrile;
##STR198## [0407]
N-{2-[1-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-qui-
nazolin-7-yl)-pyrrolidin-3-yl]-2-[(2-cyano-ethyl)-ethyl-amino]-ethyl}-acet-
amide; ##STR199## [0408]
N-{2-[(2-Cyano-ethyl)-ethyl-amino]-2-[1-(1-cyclopropyl-8-methoxy-2,4-diox-
o-1,2,3,4-tetrahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-ethyl}-acetamide;
##STR200## [0409]
N-{2-[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quin-
azolin-7-yl)-pyrrolidin-3-yl]-2-[(2-cyano-ethyl)-ethyl-amino]-ethyl}-aceta-
mide; ##STR201## [0410]
N-{2-[(2-Cyano-ethyl)-ethyl-amino]-2-[1-(1-cyclopropyl-8-methyl-2,4-dioxo-
-1,2,3,4-tetrahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-ethyl}-acetamide;
##STR202## [0411]
3-{1-[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quin-
azolin-7-yl)-azetidin-3-yl]-propylamino}-propionitrile; ##STR203##
[0412]
3-{1-[1-(1-Cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quin-
azolin-7-yl)-azetidin-3-yl]-propylamino}-propionitrile; ##STR204##
[0413]
3-{[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydr-
o-quinazolin-7-yl)-3-methyl-azetidin-3-ylmethyl]-amino}-propionitrile;
##STR205## [0414]
3-{[1-(1-Cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-y-
l)-3-methyl-azetidin-3-ylmethyl]-amino}-propionitrile; ##STR206##
[0415]
3-{1-[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahy-
dro-quinazolin-7-yl)-azetidin-3-yl]-cyclopropylamino}-propionitrile;
##STR207## [0416]
3-{1-[1-(1-Cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-
-yl)-azetidin-3-yl]-cyclopropylamino}-propionitrile; ##STR208##
[0417]
3-{[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinaz-
olin-7-yl)-3-ethyl-azetidin-3-ylmethyl]-amino}-propionitrile; or
##STR209## [0418]
3-{[1-(1-Cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-y-
l)-3-ethyl-azetidin-3-ylmethyl]-amino}-propionitrile.
[0419] A compound of formula IV: ##STR210## [0420] or a
pharmaceutically acceptable salt thereof, wherein: [0421] X is N or
C, provided that when X is N, R.sub.5 is absent at that position;
[0422] n is 0, 1, or 2; [0423] R.sub.1 is (C.sub.1-C.sub.6)alkyl,
[0424] halo(C.sub.1-C.sub.6)alkyl, [0425]
(C.sub.3-C.sub.6)cycloalkyl, [0426] halo(C.sub.3-C.sub.6)cycloalkyl
[0427] aryl, and [0428] heteroaryl; [0429]
CH.sub.2(C.sub.3-C.sub.6)cycloalkyl; [0430] R.sub.2 is H, [0431]
NH.sub.2, ##STR211## [0432] NH(C.sub.1-C.sub.6)alkyl, [0433]
NH(C.sub.3-C.sub.6)cycloalkyl, [0434] NH-aryl, [0435]
NH-heteroaryl, [0436] NHSO.sub.2--(C.sub.1-C.sub.6)alkyl, [0437]
NHSO.sub.2-aryl, [0438] NHSO.sub.2-heteroaryl, ##STR212## [0439]
wherein g is an integer from 1 to 10, Q is O, NH, or is absent, and
R.sub.2a and R.sub.2a' are each independently H or
(C.sub.1-C.sub.6)alkyl, or taken together with the carbons to which
they are attached form a 3, 4, 5, or 6-membered substituted or
unsubstituted ring, and R.sub.2b is (C.sub.1-C.sub.6)alkyl, aryl,
or heteroaryl, ##STR213## [0440] wherein R.sub.2a and R.sub.2a' are
as defined above, ##STR214## [0441] wherein indicates the point of
attachment, p is 0 or 1, and [0442] R.sub.2C is H, [0443]
(C.sub.1-C.sub.6)alkyl, [0444] O(C.sub.1-C.sub.6)alkyl, [0445]
(C.sub.3-C.sub.7)cycloalkyl, [0446] aryl, [0447] heterocyclo,
[0448] heteroaryl, or ##STR215## [0449] wherein R.sub.2a, R.sub.2b,
and Q, are as defined above, and h and n are each independently
integers from 0 to 10, and Y is OH, OPO(OH).sub.2,
OPO(O(C.sub.1-C.sub.6)).sub.2, or NR.sub.2dR.sub.2e, wherein
R.sub.2d and R.sub.2e are each independently H,
(C.sub.1-C.sub.6)alkyl, or (C.sub.3-C.sub.7)cycloalkyl, ##STR216##
[0450] wherein q is 0 or 1, R.sub.2f and R.sub.2f ' are each
independently H, (C.sub.1-C.sub.6)alkyl, aryl, or heteroaryl, or
taken together with the carbon to which they are attached form a 3,
4, 5, or 6 membered substituted or unsubstituted ring, and R.sub.2g
is [0451] (C.sub.1-C.sub.6)alkyl, [0452]
(C.sub.3-C.sub.7)cycloalkyl, [0453] aryl, or [0454] heterocyclo, or
[0455] heteroaryl; [0456] R.sub.3, R.sub.4, and R.sub.5 are each
independently H, [0457] halo, [0458] NH.sub.2, [0459]
(C.sub.1-C.sub.6)alkyl, [0460] halo(C.sub.1-C.sub.6)alkyl, [0461]
(C.sub.1-C.sub.6)alkoxy, or [0462] halo(C.sub.1-C.sub.6)alkoxy
[0463] nitrile; or [0464] R.sub.1 , and R.sub.5 taken together with
the carbons to which they are attached form a substituted or
unsubstituted 5- or 6-membered substituted or unsubstituted ring
containing 0, 1, or 2 heteroatoms selected from O, S, SO, SO.sub.2,
or NR.sub.x, wherein R.sub.x is H or (C.sub.1-C.sub.6)alkyl; and
[0465] z is 0, 1, or 2; [0466] R.sub.a and R.sub.b are each
independently H, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
halo(C.sub.1-C.sub.6)alkyl, halo, or R.sub.a and R.sub.b taken
together with the carbon to which they are attached form a 3, 4, 5
or 6-membered substituted or unsubstituted ring; [0467] R' is H,
[0468] halo, [0469] (C.sub.1-C.sub.6)alkyl, [0470]
O(C.sub.1-C.sub.6)alkyl [0471] halo(C.sub.1-C.sub.6)alkyl, [0472]
aryl, or [0473] heteroaryl; [0474] R.sub.c and R.sub.d are each
independently H, [0475] (C.sub.1-C.sub.6)alkylnitrile; ##STR217##
[0476] (C.sub.1-C.sub.6)alkyl, [0477] (C.sub.3-C.sub.6)cycloalkyl,
[0478] heteroaryl, [0479] SO.sub.2--(C.sub.1-C.sub.6)alkyl, [0480]
SO.sub.2-aryl, [0481] SO.sub.2-heteroaryl, ##STR218## [0482]
wherein g is an integer from 1 to 10, Q is as defined above, and
R.sub.2a and R.sub.2a' are each independently H or
(C.sub.1-C.sub.6)alkyl, or taken together with the carbons to which
they are attached form a 3, 4, 5, or 6-membered substituted or
unsubstituted ring, and R.sub.2b is (C.sub.1-C.sub.6)alkyl, aryl,
or heteroaryl, ##STR219## [0483] wherein R.sub.2a and R.sub.2a' are
as defined above, ##STR220## [0484] wherein indicates the point of
attachment, p is 0 or 1, and [0485] R.sub.2c is H, [0486]
(C.sub.1-C.sub.6)alkyl, [0487] O(C.sub.1-C.sub.6)alkyl, [0488]
(C.sub.3-C.sub.7)cycloalkyl, [0489] aryl, [0490] heterocyclo,
[0491] heteroaryl, or ##STR221## [0492] wherein R.sub.2a, R.sub.2b,
and Q are as defined above, and h and j are each independently
integers from 0 to 10, and Y is OH, OPO(OH).sub.2,
OPO(O(C.sub.1-C.sub.6)).sub.2, or NR.sub.2dR.sub.2e, wherein
R.sub.2d and R.sub.2e are each independently H,
(C.sub.1-C.sub.6)alkyl, or (C.sub.3-C.sub.7)cycloalkyl, ##STR222##
[0493] wherein q is 0 or 1, R.sub.2f and R.sub.2f ' are each
independently H, (C.sub.1-C.sub.6)alkyl, aryl, or heteroaryl, or
taken together with the carbon to which they are attached form a 3,
4, 5, or 6 membered substituted or unsubstituted ring, and R.sub.2g
is [0494] (C.sub.1-C.sub.6)alkyl, [0495]
(C.sub.3-C.sub.7)cycloalkyl, [0496] aryl, or [0497] heterocyclo, or
[0498] heteroaryl; and [0499] R.sub.e and R.sub.f are each
independently H, C.sub.1-C.sub.6 alkyl, haloalkyl, halo, or R.sub.e
and R.sub.f taken together with the carbon to which they are
attached form a 3, 4, 5 or 6-membered substituted or unsubstituted
ring.
[0500] What is also provided is a compound which is: ##STR223##
[0501]
3-Amino-3-[1-(5-amino-8-fluoro-3-methyl-4,6-dioxo-2,3,5,6-tetrahydro-4H--
1-oxa-3a,5-diaza-phenalen-9-yl)-pyrrolidin-3-yl]-propionitrile;
##STR224## [0502]
3-Amino-3-[1-(8-fluoro-3-methyl-4,6-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,-
5-diaza-phenalen-9-yl)-pyrrolidin-3-yl]-propionitrile; ##STR225##
[0503]
3-Amino-3-[1-(3-amino-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-te-
trahydro-pyrido[2,3-d]pyrimidin-7-yl)-pyrrolidin-3-yl]-propionitrile;
##STR226## [0504]
3-Amino-3-[1-(1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-pyrido[-
2,3-d]pyrimidin-7-yl)-pyrrolidin-3-yl]-propionitrile; ##STR227##
[0505]
3-Amino-3-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-
-tetrahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-propionitrile;
##STR228## [0506]
3-Amino-3-[1-(1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4--
tetrahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-propionitrile;
##STR229## [0507]
3-Amino-3-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1-
,2,3,4-tetrahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-propionitrile;
##STR230## [0508]
3-Amino-3-[1-(1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydr-
o-quinazolin-7-yl)-pyrrolidin-3-yl]-propionitrile; ##STR231##
[0509]
3-Amino-3-[1-(3-amino-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-
-quinazolin-7-yl)-pyrrolidin-3-yl]-propionitrile; ##STR232## [0510]
b
3-Amino-3-[1-(1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-quinazo-
lin-7-yl)-pyrrolidin-3-yl]-propionitrile; ##STR233## [0511]
3-Amino-3-[1-(3-amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydr-
o-quinazolin-7-yl)-pyrrolidin-3-yl]-propionitrile; ##STR234##
[0512]
3-Amino-3-[1-(1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinaz-
olin-7-yl)-pyrrolidin-3-yl]-propionitrile; ##STR235## [0513]
3-Amino-3-[1-(3-amino-1-cyclopropyl-g-methyl-2,4-oxo-1,2,3,4-tetrahydro-q-
uinazolin-7-yl)-pyrrolidin-3-yl]-propionitrile; ##STR236## [0514]
3-Amino-3-[1-(1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazo-
lin-7-yl)-pyrrolidin-3-yl]-propionitrile; ##STR237## [0515]
3-Amino-3-[1-(3,5-diamino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-pyrrolidin-3-yl]-propionitrile; ##STR238##
[0516]
3-Amino-3-[1-(5-amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-t-
etrahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-propionitrile;
##STR239## [0517]
3-Amino-3-[1-(3,5-diamino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,-
4-tetrahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-propionitrile;
##STR240## [0518]
3-Amino-3-[1-(5-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-t-
etrahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-propionitrile;
##STR241## [0519]
3-Amino-3-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo--
1,2,3,4-tetrahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-propioni-
trile; ##STR242## [0520]
3-Amino-3-[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-propionitrile;
##STR243## [0521]
3-Amino-3-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-t-
etrahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-propionitrile;
##STR244## [0522]
3-Amino-3-[1-(1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydr-
o-quinazolin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-propionitrile;
##STR245## [0523]
3-Amino-3-[1-(3-amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydr-
o-quinazolin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-propionitrile;
##STR246## [0524]
3-Amino-3-[1-(1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinaz-
olin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-propionitrile; ##STR247##
[0525]
3-Amino-3-[1-(3-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-te-
trahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-propionitrile;
##STR248## [0526]
3-Amino-3-[1-(1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazo-
lin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-propionitrile; ##STR249##
[0527]
3-Amino-3-[1-(3,5-diamino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3-
,4-tetrahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-propionitrile-
; ##STR250## [0528]
3-Amino-3-[1-(5-amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydr-
o-quinazolin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-propionitrile;
##STR251## [0529]
3-Amino-3-[1-(3,5-diamino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrah-
ydro-quinazolin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-propionitrile;
##STR252## [0530]
3-Amino-3-[1-(5-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
-quinazolin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-propionitrile;
##STR253## [0531]
3-Amino-3-[1-(3-amino-1-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazol-
in-7-yl)-pyrrolidin-3-yl]-propionitrile; ##STR254## [0532]
3-Amino-3-[1-(1-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-yl)-
-pyrrolidin-3-yl]-propionitrile; ##STR255## [0533]
3-[1-(3-Amino-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-quinazo-
lin-7-yl)-pyrrolidin-3-yl]-3-methylamino-propionitrile; ##STR256##
[0534]
3-[1-(1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-quinazo-
lin-7-yl)-pyrrolidin-3-yl]-3-methylamino-propionitrile; ##STR257##
[0535]
3-[1-(5-Amino-8-fluoro-3-methyl-4,6-dioxo-2,3,5,6-tetrahydro-4H-1-
-oxa-3a,5-diaza-phenalen-9-yl)-pyrrolidin-3-yl]-3-methylamino-propionitril-
e; ##STR258## [0536]
3-[1-(8-Fluoro-3-methyl-4,6-dioxo-2,3,5,6-tetrahydro-4H-1-oxa-3a,5-diaza--
phenalen-9-yl)-pyrrolidin-3-yl]-3-methylamino-propionitrile;
##STR259## [0537]
3-[1-(3-Amino-1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-
-pyrido[2,3-d]pyrimidin-7-yl)-pyrrolidin-3-yl]-3-methylamino-propionitrile-
; ##STR260## [0538]
3-[1-(1-cyclopropyl-6-fluoro-2,4-dioxo-1,2,3,4-tetrahydro-pyrido[2,3-d]py-
rimidin-7-yl)-pyrrolidin-3-yl]-3-methylamino-propionitrile;
##STR261## [0539]
3-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4--
tetrahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-3-methylamino-propionitrile;
##STR262## [0540]
3-[1-(1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quina-
zolin-7-yl)-pyrrolidin-3-yl]-3-methylamino-propionitrile;
##STR263## [0541]
3-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-t-
etrahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-3-methylamino-propionitrile;
##STR264## [0542]
3-[1-(1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinaz-
olin-7-yl)-pyrrolidin-3-yl]-3-methylamino-propionitrile; ##STR265##
[0543]
3-[1-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydr-
o-quinazolin-7-yl)-pyrrolidin-3-yl]-3-methylamino-propionitrile;
##STR266## [0544]
3-[1-(1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-y-
l)-pyrrolidin-3-yl]-3-methylamino-propionitrile; ##STR267## [0545]
3-[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazo-
lin-7-yl)-pyrrolidin-3-yl]-3-methylamino-propionitrile; ##STR268##
[0546]
3-[1-(1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazo-
lin-7-yl)-pyrrolidin-3-yl]-3-methylamino-propionitrile; ##STR269##
[0547]
3-[1-(3,5-Diamino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-pyrrolidin-3-yl]-3-methylamino-propionitrile;
##STR270## [0548]
3-[1-(5-amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinaz-
olin-7-yl)-pyrrolidin-3-yl]-3-methylamino-propionitrile; ##STR271##
[0549]
3-[1-(3,5-Diamino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrah-
ydro-quinazolin-7-yl)-pyrrolidin-3-yl]-3-methylamino-propionitrile;
##STR272## [0550]
3-[1-(5-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazo-
lin-7-yl)-pyrrolidin-3-yl]-3-methylamino-propionitrile; ##STR273##
[0551]
3-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4--
tetrahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-3-methylamino-pr-
opionitrile; ##STR274## [0552]
3-[1-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quina-
zolin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-3-methylamino-propionitrile;
##STR275## [0553]
3-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydr-
o-quinazolin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-3-methylamino-propionitri-
le; ##STR276## [0554]
3-[1-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinaz-
olin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-3-methylamino-propionitrile;
##STR277## [0555]
3-[1-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinaz-
olin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-3-methylamino-propionitrile;
##STR278## [0556]
3-[1-(1-Cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-y-
l)-pyrrolidin-3-yl]-2,2-dimethyl-3-methylamino-propionitrile;
##STR279## [0557]
3-[1-(3-Amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydr-
o-quinazolin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-3-methylamino-propionitri-
le; ##STR280## [0558]
3-[1-(1-Cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-yl-
)-pyrrolidin-3-yl]-2,2-dimethyl-3-methylamino-propionitrile;
##STR281## [0559]
3-[1-(3,5-Diamino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-3-methylamino-propion-
itrile; ##STR282## [0560]
3-[1-(5-amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinaz-
olin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-3-methylamino-propionitrile;
##STR283## [0561]
3-[1-(3,5-Diamino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-qui-
nazolin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-3-methylamino-propionitrile;
or ##STR284## [0562]
3-[1-(5-amino-1-cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazo-
lin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-3-methylamino-propionitrile.
[0563] What is also provided is a compound of formula V or VI
##STR285## [0564] or a pharmaceutically acceptable salt thereof,
wherein: [0565] X is N or C, provided that when X is N, R.sub.5 is
absent at that position; [0566] n and q are each independently 0,
1, or 2; [0567] R.sub.1 is (C.sub.1-C.sub.6)alkyl, [0568]
halo(C.sub.1-C.sub.6)alkyl, [0569] (C.sub.3-C.sub.6)cycloalkyl,
[0570] halo(C.sub.3-C.sub.6)cycloalkyl [0571] aryl, and [0572]
heteroaryl; [0573] CH.sub.2(C.sub.3-C.sub.6)cycloalkyl; [0574]
R.sub.2 is H, [0575] NH.sub.2, ##STR286## [0576]
NH(C.sub.1-C.sub.6)alkyl, [0577] NH(C.sub.3-C.sub.6)cycloalkyl,
[0578] NH-aryl, [0579] NH-heteroaryl, [0580]
NHSO.sub.2--(C.sub.1-C.sub.6)alkyl, [0581] NHSO.sub.2-aryl, [0582]
NHSO.sub.2-heteroaryl, ##STR287## [0583] wherein g is an integer
from 1 to 10, Q is O, NH, or is absent, and R.sub.2a' and R.sub.2a
are each independently H or (C.sub.1-C.sub.6)alkyl, or taken
together with the carbons to which they are attached form a 3, 4,
5, or 6-membered substituted or unsubstituted ring, and R.sub.2b is
(C.sub.1-C.sub.6)alkyl, aryl, or heteroaryl, ##STR288## [0584]
wherein R.sub.a and R.sub.2a' are as defined above, ##STR289##
[0585] wherein indicates the point of attachment, p is 0 or 1, and
[0586] R.sub.2c is H, [0587] (C.sub.1-C.sub.6)alkyl, [0588]
O(C.sub.1-C.sub.6)alkyl, [0589] (C.sub.3-C.sub.7)cycloalkyl, [0590]
aryl, [0591] heterocyclo, [0592] heteroaryl, or ##STR290## [0593]
wherein R.sub.2a, R.sub.2b, and Q, are as defined above, and h and
n are each independently integers from 0 to 10, and Y is OH,
OPO(OH).sub.2, OPO(O(C.sub.1-C.sub.6)).sub.2, or NR.sub.2dR.sub.2e,
wherein R.sub.2d and R.sub.2e are each independently H,
(C.sub.1-C.sub.6)alkyl, or (C.sub.3-C.sub.7)cycloalkyl, ##STR291##
[0594] wherein q is 0 or 1, R.sub.2f and R.sub.2f' are each
independently H, (C.sub.1-C.sub.6)alkyl, aryl, or heteroaryl, or
taken together with the carbon to which they are attached form a 3,
4, 5, or 6 membered substituted or unsubstituted ring, and R.sub.2g
is [0595] (C.sub.1-C.sub.6)alkyl, [0596]
(C.sub.3-C.sub.7)cycloalkyl, [0597] aryl, or [0598] heterocyclo, or
[0599] heteroaryl; [0600] R.sub.3, R.sub.4, and R.sub.5 are each
independently H, [0601] halo, [0602] NH.sub.2, [0603]
(C.sub.1-C.sub.6)alkyl, [0604] halo(C.sub.1-C.sub.6)alkyl, [0605]
(C.sub.1-C.sub.6)alkoxy, or [0606] halo(C.sub.1-C.sub.6)alkoxy
[0607] nitrile; or [0608] R.sub.1 and R.sub.5 taken together with
the carbons to which they are attached form a substituted or
unsubstituted 5- or 6-membered substituted or unsubstituted ring
containing 0, 1, or 2 heteroatoms selected from O, S, SO, SO.sub.2,
or NR.sub.x, wherein R.sub.x is H or (C.sub.1-C.sub.6)alkyl; and
[0609] q is 0, 1, 2, or 3 and z is 0, 1, or 2; [0610] R.sub.b is H,
(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, halo, or
R.sub.a and R.sub.b taken together with the carbon to which they
are attached form a 3, 4, 5 or 6-membered substituted or
unsubstituted ring; [0611] R', R'', R''', and R'''' are each
independently H, [0612] (C.sub.1-C.sub.6) alkyl, [0613]
--O(C.sub.1-C.sub.6)alkyl, [0614] halo(C.sub.1-C.sub.6)alkyl,
[0615] aryl, or [0616] heteroaryl; [0617] B is ##STR292## [0618]
provided that when B is ##STR293## [0619] R' is not
O(C.sub.1-C.sub.6)alkyl, and wherein indicates the point of
attachment, and [0620] R.sub.c and R.sub.d are each independently
H, [0621] (C.sub.1-C.sub.6)alkylnitrile; ##STR294## [0622]
(C.sub.1-C.sub.6)alkyl, [0623] (C.sub.3-C.sub.6)cycloalkyl, [0624]
heteroaryl, [0625] SO.sub.2--(C.sub.1-C.sub.6)alkyl, [0626]
SO.sub.2-aryl, [0627] SO.sub.2-heteroaryl, ##STR295## [0628]
wherein g is an integer from 1 to 10, Q is as defined above, and
R.sub.2a and R.sub.2a' are each independently H or
(C.sub.1-C.sub.6)alkyl, or taken together with the carbons to which
they are attached form a 3, 4, 5, or 6-membered substituted or
unsubstituted ring, and R.sub.2b is (C.sub.1-C.sub.6)alkyl, aryl,
or heteroaryl, ##STR296## [0629] wherein R.sub.2a and R.sub.2a' are
as defined above, ##STR297## [0630] wherein indicates the point of
attachment, p is 0 or 1, and [0631] R.sub.2c is H, [0632]
(C.sub.1-C.sub.6)alkyl, [0633] O(C.sub.1-C.sub.6)alkyl, [0634]
(C.sub.3-C.sub.7)cycloalkyl, [0635] aryl, [0636] heterocyclo,
[0637] heteroaryl, or ##STR298## [0638] wherein R.sub.2a, R.sub.2b,
and Q are as defined above, and h and j are each independently
integers from 0 to 10, and Y is OH, OPO(OH).sub.2,
OPO(O(C.sub.1-C.sub.6)).sub.2, or NR.sub.2dR.sub.2e, wherein
R.sub.2d and R.sub.2e are each independently H,
(C.sub.1-C.sub.6)alkyl, or (C.sub.3-C.sub.7)cycloalkyl, ##STR299##
[0639] wherein q is 0 or 1, R.sub.2f and R.sub.2f' are each
independently H, (C.sub.1-C.sub.6)alkyl, aryl, or heteroaryl, or
taken together with the carbon to which they are attached form a 3,
4, 5, or 6 membered substituted or unsubstituted ring, and R.sub.2g
is [0640] (C.sub.1-C.sub.6)alkyl, [0641]
(C.sub.3-C.sub.7)cycloalkyl, [0642] aryl, or [0643] heterocyclo, or
[0644] heteroaryl; [0645] R.sub.e and R.sub.f are each
independently H, C.sub.1-C.sub.6 alkyl, haloalkyl, halo, or R.sub.e
and R.sub.f taken together with the carbon to which they are
attached form a 3, 4, 5 or 6-membered substituted or unsubstituted
ring; [0646] R.sub.g and R.sub.h are each independently H,
C.sub.1-C.sub.6 alkyl, haloalkyl, or taken together with the carbon
to which they are attached to form a 3, 4, 5 or 6-membered
substituted or unsubstituted ring; and [0647] R.sub.j and R.sub.k
are each independently H, (C.sub.1-C.sub.6)alkyl, haloalkyl,
(C.sub.1-C.sub.6)alkyl-NR.sub.cR.sub.d,
(C.sub.1-C.sub.6)alkyl-OR.sub.c, aryl, heteroaryl, heterocycle,
##STR300## [0648] wherein Z is O or NR.sub.c, or R.sub.j and
R.sub.k taken together with the carbon to which they are attached
to form a 3, 4, 5 or 6-membered substituted or unsubstituted
ring.
[0649] What is also provided is a compound which is ##STR301##
[0650]
3-[2-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-octahydro-cyclopenta[c]pyrrol-4-ylamino]-propionitrile-
; ##STR302## [0651]
3-[2-(3-Amino-1-cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinaz-
olin-7-yl)-octahydro-cyclopenta[c]pyrrol-4-ylamino]-propionitrile;
##STR303## [0652]
3-[2-(1-Cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinaz-
olin-7-yl)-octahydro-cyclopenta[c]pyrrolyl-4-ylamino]-propionitrile;
##STR304## [0653]
3-[2-(1-Cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quina-
zolin-7-yl)-octahydro-cyclopenta[c]pyrrol-4-ylamino]-propionitrile;
##STR305## [0654]
3-[2-(1-Cyclopropyl-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-7-y-
l)-octahydro-cyclopenta[c]pyrrol-4-ylamino]-propionitrile; or
##STR306## [0655]
3-[2-(1-Cyclopropyl-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinaz-
olin-7-yl)-octahydro-cyclopenta[c]pyrrol-4-ylamino]-propionitrile.
[0656] What is also provided is a pharmaceutical formulation
comprising a compound of one of formula I admixed with a
pharmaceutically acceptable diluent, carrier, or excipient.
[0657] What is also provided is a method of treating a bacterial
infection in a mammal, comprising administering to a mammal in need
thereof an effective amount of a compound of formula I.
DETAILED DESCRIPTION OF THE INVENTION
[0658] Reference will now be made in detail to presently preferred
compositions or embodiments and methods of the invention, which
constitute the best modes of practicing the invention presently
known to the inventors.
[0659] The term "alkyl" as used herein refers to a linear or
branched hydrocarbon of from 1 to 6 carbon atoms and includes, for
example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,
isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like. The alkyl
group can also be substituted with one or more of the substitutents
selected from lower (C.sub.1-C.sub.6)alkoxy,
(C.sub.1-C.sub.6)thioalkoxy, halogen, aryl, heteroaryl, oxo, thio,
--OH, --SH, --F, --CF.sub.3, --OCF.sub.3, --NO.sub.2, --CO.sub.2H,
--CO.sub.2(C.sub.1-C.sub.6)alkyl, or ##STR307##
[0660] The term "(C.sub.3-C.sub.6)cycloalkyl" means a hydrocarbon
ring containing from 3 to 6 carbon atoms, for example, cyclopropyl,
cyclobutyl, cyclopentyl, or cyclohexyl. Where possible, the
cycloalkyl group may contain double bonds, for example,
3-cyclohexen-1-yl. The cycloalkyl ring may be unsubstituted or
substituted by one or more substitutents selected from alkyl,
alkoxy, thioalkoxy, hydroxy, thiol, halogen, formyl, carboxyl,
--CO.sub.2(C.sub.1-C.sub.6)alkyl, --CO(C.sub.1-C.sub.6)alkyl, aryl,
heteroaryl, wherein alkyl, aryl, and heteroaryl are as defined
herein, or as indicated above for alkyl. Examples of substituted
cycloalkyl groups include fluorocyclopropyl.
[0661] The term "halo" includes chlorine, fluorine, bromine, and
iodine.
[0662] The term "haloalkyl" means a (C.sub.1-C.sub.6)alkyl group
substituted with one or more halo.
[0663] The term "aryl" means a cyclic or polycyclic aromatic ring
having from 5 to 12 carbon atoms, and being unsubstituted or
substituted with one or more of the substitutent groups recited
above for alkyl groups including, halogen, nitro, cyano --OH, --SH,
--F, --CF.sub.3, --OCF.sub.3 ##STR308## --CO.sub.2C.sub.1-C.sub.6
alkyl, or --SO.sub.2alkyl. Examples include, but are not limited to
phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,
2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl,
3-methoxyphenyl, 4-methoxyphenyl, 2-chloro-3-methylphenyl,
2-chloro-4-methylphenyl, 2-chloro-5-methylphenyl,
3-chloro-2-methylphenyl, 3-chloro-4-methylphenyl,
4-chloro-2-methylphenyl, 4-chloro-3-methylphenyl,
5-chloro-2-methylphenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl,
3,4-dichlorophenyl, 2,3-dimethylphenyl, 3,4-dimethylphenyl,
naphthyl, 4-thionaphthyl, tetralinyl, anthracinyl, phenanthrenyl,
benzonaphthenyl, fluorenyl, 2-acetamidofluoren-9-yl, and
4'-bromobiphenyl.
[0664] The term "heteroaryl" means an aromatic cyclic or polycyclic
ring system having from 1 to 4 heteroatoms selected from N, O, and
S. Typical heteroaryl groups include 2- or 3-thienyl, 2- or
3-furanyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or
5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4, or 5-isothiazolyl, 2-,
4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or
5-1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3-, or
4-pyridinyl, 3-, 4-, or 5-pyridazinyl, 2-pyrazinyl, 2-, 4-, or
5-pyrimidinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-,
5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4,5-, 6-, or 7-indolyl, 2-,
3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or
7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-,
6-, or 7-benzothiazolyl. The heteroaryl groups may be unsubstituted
or substituted by 1 to 3 substitutents selected from those
described above for alkyl, alkenyl, and alkynyl, for example,
cyanothienyl and formylpyrrolyl. Preferred aromatic fused
heterocyclic rings of from 8 to 10 atoms include but are not
limited to 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-,
6-, 7-, or 8-isoquinolinyl-, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-,
3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or
7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-,
6-, or 7-benzothiazolyl. Heteroaryl also includes 2- and
3-aminomethylfuran, 2- and 3-aminomethylthiophene and the like.
[0665] The term "heterocyclic" means a monocyclic, fused, bridged,
or spiro bicyclic heterocyclic ring systems. Monocyclic
heterocyclic rings contain from about 3 to 12 ring atoms, with from
1 to 5 heteroatoms selected from N, O, and S, and preferably from 3
to 7 member atoms, in the ring. Bicyclic heterocyclics contain from
about 5 to about 17 ring atoms, preferably from 5 to 12 ring atoms.
Bicyclic heterocyclic rings may be fused, spiro, or bridged ring
systems. Examples of heterocyclic groups include cyclic ethers
(oxiranes) such as ethyleneoxide, tetrahydrofuran, dioxane, and
substituted cyclic ethers, wherein the substitutents are those
described above for the alkyl and cycloalkyl groups. Typical
substituted cyclic ethers include propyleneoxide, phenyloxirane
(styrene oxide), cis-2-butene-oxide (2,3-dimethyloxirane),
3-chlorotetrahydrofuran, 2,6-dimethyl-1,4-dioxane, and the like.
Heterocycles containing nitrogen are groups such as pyrrolidine,
piperidine, piperazine, tetrahydrotriazine, tetrahydropyrazole, and
substituted groups such as 3-aminopyrrolidine,
4-methylpiperazin-1-yl, and the like. Typical sulfur containing
heterocycles include tetrahydrothiophene, dihydro-1,3-dithiol-2-yl,
and hexahydrothiophenyl and substituted groups such as aminomethyl
thiophene. Other commonly employed heterocycles include
dihydro-oxathiol-4-yl, dihydro-1H-isoindole, tetrahydro-oxazolyl,
tetrahydro-oxadiazolyl, tetrahydrodioxazolyl,
tetrahydrooxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl,
morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl,
octahydrobenzofuranyl, octahydrobenzimidazolyl, and
octahydrobenzothiazolyl. For heterocycles containing sulfur, the
oxidized sulfur heterocycles containing SO or SO.sub.2 groups are
also included. Examples include the sulfoxide and sulfone forms of
tetrahydrothiophene.
[0666] In some cases, to prepare the compounds of the invention
disclosed herein, protecting groups may have been used to allow
synthetic manipulation of one functional group in the presence of
other functional groups. The appropriate use and choice of
protecting groups is well-known by one skilled in the art. It is
also to be understood that such groups not only serve to protect
chemically reactive sites, but also to enhance solubility or
otherwise change physical properties. A good general reference for
protecting group preparation and deprotection is Greene, Theodora,
Protective Groups in Organic Synthesis; Wiley: New York, USA, 1991
and later editions. Thus, it is to be further understood that
invention compounds characterized by the presence of a protecting
group as disclosed and described in Greene are also to be
considered invention compounds.
[0667] When a bond is represented by a symbol such as this is meant
to represent that the bond may be absent or present provided that
the resultant compound is stable and of satisfactory valency.
[0668] When a bond is represented by a line such as this is meant
to represent that the bond is the point of attachment between two
molecular subunits.
[0669] The term "patient" means all mammals, including humans.
Other examples of patients include cows, dogs, cats, goats, sheep,
pigs, and rabbits.
[0670] A "therapeutically effective amount" is an amount of a
compound of the present invention that, when administered to a
patient, provides the desired effect; i.e., lessening in the
severity of the symptoms associated with a bacterial infection.
[0671] It will be appreciated by those skilled in the art that
compounds of the invention having one or more chiral centers may
exist in and be isolated in optically active and racemic forms.
Some compounds may exhibit polymorphism. It is to be understood
that the present invention encompasses any racemic,
optically-active, polymorphic, geometric, or stereoisomeric form,
or mixtures thereof, of a compound of the invention, which possess
the useful properties described herein, it being well known in the
art how to prepare optically active forms (for example, by
resolution of the racemic form by recrystallization techniques, by
synthesis from optically-active starting materials, by chiral
synthesis, or by chromatographic separation using a chiral
stationary phase) and how to determine activity or cytotoxicity
using the standard tests described herein, or using other similar
tests which are well known in the art.
[0672] Certain compounds of the invention are also useful as
intermediates for preparing other compounds of the invention. Thus,
a compound wherein R.sub.2 is BF.sub.2, can be hydrolyzed to form
another compound of the invention wherein R.sub.2 is H.
[0673] Some of the compounds of Formula I are capable of further
forming pharmaceutically acceptable acid-addition and/or base
salts. All of these forms are within the scope of the present
invention. Thus, pharmaceutically acceptable acid addition salts of
the compounds of Formula I include salts derived from nontoxic
inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric,
hydrobromic, hydriodic, hydrofluoric, phosphorous, and the like, as
well as the salts derived from nontoxic organic acids, such as
aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic
acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids,
aliphatic and aromatic sulfonic acids, etc. Such salts thus include
sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate,
phosphate, monohydrogenphosphate, dihydrogenphosphate,
metaphosphate, pyrophosphate, acetate, trifluoroacetate,
propionate, caprylate, isobutyrate, oxalate, malonate, succinates
suberate, sebacate, fumarate, maleate, mandelate, benzoate,
chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate,
benzensoulfonate, toluenesulfonate, phenylacetate, citrate,
lactate, maleate, tartrate, methanesulfonate, and the like. Also
contemplated are salts of amino acids such as arginate and the like
and gluconate, galacturonate (see, for example, Berge, S. M. et.
al., "Pharmaceutical Salts," Journal of Pharmaceutical Science,
1977; 66:1-19).
[0674] The acid addition salt of said basic compounds are prepared
by contacting the free base form with a sufficient amount of the
desired acid to produce the salt in the conventional manner.
[0675] Pharmaceutically acceptable base addition salts are formed
with metals or amines, such as alkali and alkaline earth metals or
organic amines. Examples of metals used as cations are sodium,
potassium, magnesium, calcium, and the like. Examples of suitable
amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, dicyclohexylamine, ethylenediamine,
N-methylglucamine, and procaine (see, for example, Berge S. M.,
supra., 1977).
[0676] The base addition salts of said acidic compounds are
prepared by contacting the free acid form with a sufficient amount
of the desired base to produce the salt in the conventional
manner.
[0677] Certain of the compounds of the present invention can exist
in unsolvated forms as well as solvated forms, including hydrated
forms. In general, the solvated forms, including hydrated forms,
are equivalent to unsolvated forms and are intended to be
encompassed within the scope of the present invention.
[0678] A "prodrug" is an inactive derivative of a drug molecule
that requires a chemical or an enzymatic biotransformation in order
to release the active parent drug in the body.
[0679] Specific and preferred values for the compounds of the
present invention are listed below for radicals, substitutents, and
ranges are for illustration purposes only, and they do not exclude
other defined values or other values within defined ranges for the
radicals and substitutents.
[0680] Unless otherwise stated or defined, abbreviations used
herein conform to the style sheet of American Chemical Society
journals.
[0681] Thus, we turn now to a compound of formula I, which has the
structure: ##STR309##
[0682] A specific value for X is N or C--OMe or C-Me. A specific
value for R.sub.1 is (C.sub.1-C.sub.6)cycloalkyl and
halo(C.sub.1-C.sub.6)cycloalkyl, aryl, or heteroaryl. A specific
value for R.sub.2 is H, NH.sub.2, ##STR310##
NH(C.sub.1-C.sub.6)alkyl, NHSO.sub.2-(C.sub.1-C.sub.6)alkyl,
NHSO.sub.2-aryl, or NHSO.sub.2-heteroaryl. A specific value for
R.sub.3 is H, Me, or NH.sub.2. A specific value for R.sub.4 is H or
halo. A specific value for R.sub.5 is halo, methyl,
trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, or
trifluoromethoxy.
[0683] In another embodiment of a compound of formula I, a specific
value for X is C--OMe or C-Me. A specific value for R.sub.1 is
(C.sub.1-C.sub.6)cycloalkyl and halo(C.sub.1-C.sub.6)cycloalkyl,
aryl, or heteroaryl. A specific value for R.sub.2 is H, NH.sub.2,
##STR311## NHSO.sub.2--(C.sub.1-C.sub.6)alkyl, NHSO.sub.2-aryl, or
NHSO.sub.2-heteroaryl. A specific value for R.sub.3 is H, Me, or
NH.sub.2. A specific value for R.sub.4 is H or F. A specific value
for X is C or N. A specific value for R.sub.5 is methyl, methoxy,
or chloro.
[0684] In another embodiment of a compound of formula I, R.sub.1,
R.sub.2, R.sub.3, and R.sub.5 are as provided in the following
structures, R.sub.1, R.sub.3, and R.sub.5 are as provided in the
following structures, and R.sub.2 is NH.sub.2 or H, R.sub.4 is H or
F, and A is ##STR312## ##STR313## ##STR314## ##STR315##
[0685] As indicated previously, in compounds of the invention, A is
##STR316## wherein q can be 0, 1, 2, or 3 and z can be 0, 1, or 2.
Specifically, z is 0, 1, 2, when q is 2 or 3; alternatively, z is 1
or 2 when q is 0, 1, 2, or 3.
[0686] Specifically, R.sub.a and R.sub.b each independently can be
H, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy,
halo(C.sub.1-C.sub.6)alkyl, halo, or R.sub.a and R.sub.b taken
together with the carbon to which they are attached form C.dbd.O,
C.dbd.NO(C.sub.1-C.sub.6)alkyl, or a 3, 4, 5 or 6-membered
substituted or unsubstituted ring. More specifically, R.sub.a and
R.sub.b are each independently H, methyl, ethyl, fluoro,
fluoromethyl, trifluoromethyl, fluorethyl, methoxy, MeO--N.dbd., or
taken together with the carbons to which they are attached form a
cyclopropyl ring.
[0687] Specifically, R', R'', R''', and R'''' each independently
can be H, (C.sub.1-C.sub.6)alkyl, --O(C.sub.1-C.sub.6)alkyl,
halo(C.sub.1-C.sub.6)alkyl, aryl, or heteroaryl. More specifically,
R', R'', R''', and R'''' are each independently H, fluoro, methyl,
ethyl, fluoromethyl, fluoroethyl, phenyl, benzyl, or methoxy.
[0688] Specifically, B is ##STR317## However, when B is ##STR318##
wherein indicates the point of attachment, R' is not
--O(C.sub.1-C.sub.6)alkyl.
[0689] Specifically, R.sub.c and R.sub.d each independently can be
H, (C.sub.1-C.sub.6)alkylnitrile, ##STR319##
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, heteroaryl,
SO.sub.2--(C.sub.1-C.sub.6)alkyl, SO.sub.2-aryl, or
SO.sub.2-heteroaryl. More specifically, R.sub.c and R.sub.d each
independently are H, methyl, or ethyl.
[0690] Specifically R.sub.e and R.sub.f each independently can be
H, C.sub.1-C.sub.6 alkyl, haloalkyl, halo, or R.sub.e and R.sub.f
taken together with the carbon to which they are attached form a 3,
4, 5 or 6-membered substituted or unsubstituted ring. More
specifically, R.sub.e and R.sub.f each independently are H, methyl,
or ethyl.
[0691] Specifically, R.sub.g and R.sub.h each independently can be
H, C.sub.1-C.sub.6 alkyl, haloalkyl, or taken together with the
carbon to which they are attached to form a 3, 4, 5 or 6-membered
substituted or unsubstituted ring. More specifically, R.sub.g and
R.sub.h each independently are H, methyl, ethyl, fluoromethyl,
difluoromethyl, trifluoroethyl, cyclopropyl, phenyl, isoxazolyl,
carboxymethyl, carboxyethyl, or ##STR320## or taken together with
the carbons tro which they are attached form ##STR321##
[0692] Specifically R.sub.j and R.sub.k each independently can be
H, (C.sub.1-C.sub.6)alkyl, haloalkyl,
(C.sub.1-C.sub.6)alkyl-NR.sub.cR.sub.d,
(C.sub.1-C.sub.6)alkyl-OR.sub.c, aryl, heteroaryl, heterocycle,
##STR322## wherein Z is O or NR.sub.c, or R.sub.j and R.sub.k taken
together with the carbon to which they are attached to form a 3, 4,
5 or 6-membered substituted or unsubstituted ring. More
specifically, R.sub.j and R.sub.k each independently are H, methyl,
ethyl, fluoromethyl, difluoromethyl, trifluoroethyl, cyclopropyl,
phenyl, isoxazolyl, carboxymethyl, carboxyethyl, or ##STR323## or
taken together with the carbons tro which they are attached form
##STR324##
[0693] Thus, in compounds of formula I wherein A is ##STR325## and
z is 0, 1, or 2. A is exemplified by any of the following
structures: ##STR326## wherein indicates the point of attachment
and B is ##STR327## or ##STR328##
[0694] Furthermore in compounds of formula I wherein A is
##STR329## or ##STR330## wherein z is 0, 1, or 2 and q is 0, 1, 2,
or 3, A is exemplified by any of the following structures:
##STR331## wherein indicates the point of attachment and B is
##STR332## or ##STR333##
[0695] As indicated previously, B can be ##STR334## or ##STR335##
wherein R.sub.c, R.sub.d, R.sub.e, R.sub.f, R.sub.g, R.sub.h,
R.sub.j, and R.sub.k and have any of the definitions provided
above. Thus B can have any of the following structures: ##STR336##
##STR337##
[0696] Thus, given the description of A and B, ##STR338## includes
any of the following structures: ##STR339## ##STR340## ##STR341##
##STR342## wherein R is CH.sub.2CH.sub.2CN.
[0697] Also given the description of A and B, ##STR343## further
includes any of the following structures: ##STR344## ##STR345##
wherein R is CH.sub.2CN.
[0698] Also given the description of A and B, ##STR346##
encompasses any of the following structures: ##STR347## wherein R
is CH.sub.2CH.sub.2CN.
[0699] Also given the description of A and B, ##STR348##
encompasses any of the following structures: ##STR349## wherein
R.sub.c is H or (C.sub.1-C.sub.6)alkyl and R is CH.sub.2CN.
[0700] We turn now to compounds of formulas II and III, which have
the structures: ##STR350##
[0701] Specific values and embodiments for compounds of formulas II
and III are as provided for compounds of formula I with respect to
q, z, X, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.a,
R.sub.b, R.sub.c, R.sub.e, R.sub.f, R.sub.g, R.sub.h, R.sub.j, and
R.sub.k.
[0702] We turn now to a compound of formula IV, which has the
structure: ##STR351##
[0703] as provided for compounds of formula I with respect to n, X,
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.a, R.sub.b,
R.sub.c, R.sub.d, R.sub.e, and R.sub.f.
[0704] We turn now to a compound of formula V or VI. ##STR352##
[0705] Specific values and embodiments for compounds of formulas V
are as provided for compounds of formula I with respect to z, q, X,
R.sub.a, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R', R'',
R''', R'''', R.sub.a, R.sub.b, R.sub.c, R.sub.e, R.sub.f, R.sub.g,
R.sub.h, R.sub.j, and R.sub.k.
Preparation of Invention Compounds
[0706] Strategies for the preparation of invention compounds are
depicted in the following Schemes.
[0707] As is readily apparent from this disclosure, compounds of
the present invention are characterized by an aminoquinazolinedione
core, covalently bound to a C-7 sidechain A-B, wherein A-B can be
##STR353## or ##STR354## As is retrosynthetically depicted in
Scheme I, the invention compounds can be prepared via coupling of a
suitably C-7 substituted aminoquinazolinedione core precursor,
wherein X is halo, triflate, or a similar reactive group known to
the skilled artisan, and an appropriately substituted azetidine,
pyrrolidine, piperidine. ##STR355##
[0708] Reflecting the synthetic strategy summarized in Scheme I,
the following section describing the preparation of the invention
compounds has several parts. The first part describes the synthesis
of the requisite aminoquinazolinedione core precursors. The second
part describes the synthesis of the requisite C-7 sidechain
precursors. The final part describes the coupling of the C-7
sidechain and aminoquinazolinedione core precursors to provide the
invention compounds, and details any further chemical elaboration
of invention compounds to produce other invention compounds.
A. Synthesis of Aminoquinazolinedione Core Precursors
[0709] The quinazolinedione core precursors that are used to
prepare the invention compounds can be prepared as described in
U.S. patent application Ser. No. 10/182,221, filed Dec. 12, 2001
and references cited therein.
B. Synthesis of C-7 Sidechains and Sidechain Precursors
[0710] 1. Preparation of ##STR356## were prepared as provided in
Scheme 1. Thus, 3-formyl-pyrrolidine-1-carboxylic acid benzyl ester
was allowed to undergo reaction with cyanomethyl-phosphonic acid
diethyl ester in the presence of cesium carbonate to provide
3-(2-cyano-vinyl)-pyrrolidine-1-carboxylic acid benzyl ester.
Ammonia or methylamine addition to
3-(2-cyano-vinyl)-pyrrolidine-1-carboxylic acid benzyl ester
provided the corresponding Michael adduct, which was subsequently
tert-butoxycarbonyl (Boc)-protected. Removal of the benzyl ester
group under conventional conditions provided the target compound as
the protected Boc analogue, which can be submitted to silica gel
chromatography to provide each diastereomer and chiral HPLC
separation to provide each enantiomer. Purification by
chromatography as described herein provides pure samples of
##STR357## as well as the associated diastereomers, for coupling.
Removal of the Boc protecting groups after coupling provides the
unprotected amines ##STR358## and ##STR359## wherein indicates a
point of attachment. ##STR360##
[0711] 2. Preparation of ##STR361## was prepared according to
Scheme 2. Thus, 1-benzhydryl-azetidine-3-carbonitrile was converted
to 1-(1-benzhydryl-azetidin-3-yl)-cyclopropylamine as provided by
Chem. Rev., 1979, Vol. 79, No. 4 and Tet. Lett. 44, 2003, 2485.
1-(1-Benzhydryl-azetidin-3-yl)-cyclopropylamine was converted to
N-[1-(1-Benzhydryl-azetidin-3-yl)-cyclopropyl]-2,2,2-trifluoro-acetamide
as provided by J. Med. Chem. 1993, vol. 36, No. 7. Hydrogenation of
N-[1-(1-benzhydryl-azetidin-3-yl)-cyclopropyl]-2,2,2-trifluoro-acetamide
provided the title compound, which can be converted to the free
amine and subsequently derivatized after the coupling reaction to
the aminoquinazolinedione core. ##STR362##
[0712] 3. Preparation of ##STR363## was prepared as provided in
Scheme 3. Thus, Grignard reaction of ethylmagnesium bromide with
1-benzhydryl-azetidin-3-one provided the corresponding alcohol,
1-benzhydryl-3-ethyl-azetidin-3-ol. Mesylation of the alcohol
moiety in 1-benzhydryl-3-ethyl-azetidin-3-ol under conventional
conditions, followed by nucleophilic addition of CN, provided
1-benzhydryl-3-ethyl-azetidine-3-carbonitrile, which was
subsequently reduced using lithium aluminum hydride (LAH) to
provide C-(1-benzhydryl-3-ethyl-azetidin-3-yl)-methylamine.
Protection of C-(1-benzhydryl-3-ethyl-azetidin-3-yl)-methylamine as
the trifluoroacetate, followed by hydrogenation, provided the
target compound, which can be converted to free amine and
subsequently deprotected after the coupling reaction to the
aminoquinazolinedione core. ##STR364##
[0713] 4. Preparation of ##STR365## was prepared as provided in
Scheme 4. Thus, 1-benzhydryl-azetidine-3-carbonitrile was
hydrolyzed under conventional conditions to provide
1-benzhydryl-azetidine-3-carboxylic acid, which was subsequently
treated with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride and N,O-dimethyl-hydroxyl-amine hydrochloride in the
presence of triethylamine to give
1-benzhydryl-azetidine-3-carboxylic acid methoxymethylamide.
Grignard addition of ethylmagnesium bromide to
1-benzhydryl-azetidine-3-carboxylic acid methoxymethylamide
provided the corresponding ketone,
1-(1-benzhydryl-azetidin-3-yl)-propan-1-one. Reductive amination of
1-(1-benzhydryl-azetidin-3-yl)-propan-1-one using ammonium acetate
and sodium cyanoborohydride, followed by treatment with
trifluoroacetic anhydride in the presence of an amine base provided
1-(1-benzhydryl-azetidin-3-yl)-propan-1-one. Hydrogenation of
1-(1-benzhydryl-azetidin-3-yl)-propan-1-one gave the target
compound, which can be converted to the free amine and subsequently
deprotected after the coupling reaction to the
aminoquinazolinedione core. ##STR366##
[0714] 5. Preparation of ##STR367## was prepared as provided in
Scheme 5. Thus, similar to the synthesis of ##STR368## as depicted
in Scheme 3, Grignard reaction of methylmagnesium bromide with
1-benzhydryl-azetidin-3-one provided the corresponding alcohol,
1-benzhydryl-3-methyl-azetidin-3-ol. Mesylation of the alcohol
moiety in 1-benzhydryl-3-methyl-azetidin-3-ol under conventional
conditions, followed by nucleophilic displacement with CN, provided
1-benzhydryl-3-methyl-azetidine-3-carbonitrile, which was
subsequently reduced using lithium aluminum hydride (LAH) to
provide C-(1-benzhydryl-3-methyl-azetidin-3-yl)-methylamine.
Protection of C-(1-benzhydryl-3-methyl-azetidin-3-yl)-methylamine
as the trifluoroacetate, followed by hydrogenation, provided the
target compound, which can be converted to free amine and
subsequently deprotected after the coupling reaction to the
aminoquinazolinedione core. ##STR369##
[0715] 6. Preparation of ##STR370##
[0716] The target compounds ##STR371## were prepared as provided in
Scheme 6. Thus, N-(trimethylsilylmethyl)-.alpha.-methylbenzylamine
was prepared from the corresponding amine using trimethylsilyl
chloride under conventional conditions. Reaction of
N-(trimethylsilylmethyl)-.alpha.-methylbenzyl amine with
formaldehyde in the presence of potassium carbonate and methanol
provided
N-(methoxymethyl)-N-(trimethylsilylmethyl)-.alpha.-methylbenzylamine,
which was subsequently converted to
1-(1-phenyl-ethyl)-pyrrolidine-3-carboxylic acid dibenzylamide as a
mixture of stereoisomers. Treatment of the amide with
ethylmagnesium bromide in the presence or Ti(OiPr).sub.4 provided
the protected target compounds as a separable mixture. The
separable diastereomers are deprotected by hydrogenation to give
the target compounds. ##STR372##
[0717] 7. Preparation of ##STR373## was prepared as provided in
Scheme 7. Thus, mesylation of S-1-benzyl-pyrrolidin-3-ol, followed
by followed by nucleophilic addition using CN.sup.-, provided
R-1-benzyl-pyrrolidine-3-carbonitrile. LAH reduction of
R-1-benzyl-pyrrolidine-3-carbonitrile provided
R--C-(1-Benzyl-pyrrolidin-3-yl)-methylamine. Boc protection of the
amine group in R--C-(1-Benzyl-pyrrolidin-3-yl)-methylamine provided
(1-benzyl-pyrrolidin-3-ylmethyl)-carbamic acid tert-butyl ester,
which was hydrogenated to provide the target compound.
##STR374##
[0718] 8. Preparation of ##STR375## was prepared as provided in
Scheme 8. Thus, treatment of
5-oxo-1-(1-phenyl-ethyl)-pyrrolidine-3-carboxylic acid methyl ester
with lithium aluminum hydride provided
[1-(1-phenyl-ethyl)-pyrrolidin-3-yl]-methanol. Treatment of
[1-(1-phenyl-ethyl)-pyrrolidin-3-yl]-methanol with
isoindole-1,3-dione in the presence of triphenyl phosphine and
diisopropyl azodicarboxylate gave the phthalimide,
2-[1-(1-phenyl-ethyl)-pyrrolidin-3-ylmethyl]-isoindole-1,3-dione.
Treatment of the phthalimide with hydrazine hydrate gave
C-[1-(1-phenyl-ethyl)-pyrrolidin-3-yl]-methylamine, which was
BOC-protected and hydrogenated to provide the target compound,
which was converted to free amine and subsequently derivatized
after the coupling reaction to the aminoquinazolinedione core.
##STR376##
[0719] 9. Preparation of ##STR377## was prepared as provided in
Scheme 9. Thus, 1-benzyl-pyrrolidine-3-carboxylic acid ethyl ester
was hydrogenated under conventional conditions to provide
pyrrolidine-3-carboxylic acid ethyl ester, which was subsequently
BOC-protected to provide pyrrolidine-1,3-dicarboxylic acid
1-tert-butyl ester 3-ethyl ester. Reduction of
pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester
provided 3-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl
ester, which was oxidized to the corresponding aldehyde
3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester under
Swern-type conditions.
3-(1-tert-butoxycarbonylamino-2-cyano-2,2-dimethyl-ethyl)-pyrrolidine-1-c-
arboxylic acid tert-butyl ester was prepared from
3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester by the
addition of lithiated isopropylcyanide to the intermediate
a-amidoalkyl sulfone. Deprotection of
3-(1-tert-butoxycarbonylamino-2-cyano-2,2-dimethyl-ethyl)-pyrrolidine-1-c-
arboxylic acid tert-butyl ester provided the title compound
3-amino-2,2-dimethyl-3-pyrrolidin-3-yl-propionitrile as the
dihydrochloride salt. ##STR378## 10. Preparation of ##STR379##
[0720] The compound was prepared as provided in WO 96/39407. 11.
Preparation of ##STR380## can be prepared as provided in Scheme 11.
Thus, [3+2] cycloaddition of cyclopent-1-enecarboxylic acid methyl
ester or the like with
benzyl-methoxymethyl-trimethylsilanylmethyl-amine under conditions
readily available to the skilled artisan and discussed herein
provides 2-benzyl-hexahydro-cyclopenta[c]pyrrole-3a-carboxylic acid
methyl ester.
[0721] Preparation of ##STR381## commences with hydride reduction
of 2-benzyl-hexahydro-cyclopenta[c]pyrrole-3a-carboxylic acid
methyl ester using an aluminum hydride or borohydride to provide
(2-benzyl-hexahydro-cyclopenta[c]pyrrol-3a-yl)-methanol. Conversion
of the alcohol moiety in
(2-benzyl-hexahydro-cyclopenta[c]pyrrol-3a-yl)-methanol to a
leaving group such as the mesylate or tosylate, followed by
displacement with a primary or secondary amine, and a protection
deprotection sequence, provides
(2-benzyl-hexahydro-cyclopenta[c]pyrrol-3a-ylmethyl)-carbamic acid
tert-butyl ester, ##STR382## Alternatively, if the reduction of the
ester moiety in
2-benzyl-hexahydro-cyclopenta[c]pyrrole-3a-carboxylic acid methyl
ester is stopped at the aldehyde oxidation state (for example, by
employing DIBALH as the reducing agent), a reductive amination
using ammonium formate or a primary alkyl amine such as methyl or
ethyl amine can be employed to provide the aminated product.
Reductive amination conditions and reagents are readily known to
the skilled artisan.
[0722] Preparation of ##STR383## commences with saponification of
the ester moiety in
2-benzyl-hexahydro-cyclopenta[c]pyrrole-3a-carboxylic acid methyl
ester top provide
2-benzyl-hexahydro-cyclopenta[c]pyrrole-3a-carboxylic acid. Curtius
rearrangement of
2-benzyl-hexahydro-cyclopenta[c]pyrrole-3a-carboxylic acid using
conditions and rearrangements readily available to the skilled
artisan provides ##STR384##
(hexahydro-cyclopenta[c]pyrrol-3a-yl)-carbamic acid tert-butyl
ester.
[0723] Preparation of ##STR385## commences with DIBALH reduction of
2-benzyl-hexahydro-cyclopenta[c]pyrrole-3a-carboxylic acid methyl
ester to provide the corresponding aldehyde. Methyleneation of the
aldehyde under Wittig- or Horner-Wadsworth-Emmons-type conditions
provides
3-(2-benzyl-hexahydro-cyclopenta[c]pyrrol-3a-yl)-acrylonitrile.
Michael addition of ammonia or a primary alkyl amine to
3-(2-benzyl-hexahydro-cyclopenta[c]pyrrol-3a-yl)-acrylonitrile
provides
[2-Cyano-1-(hexahydro-cyclopenta[c]pyrrol-3a-yl)-ethyl]-carbamic
acid tert-butyl ester. ##STR386## C. Coupling of C-7 Sidechain and
Aminoquinazolinedione Core Precursors to Provide Invention
Compounds and Invention Compound Precursors
[0724] Coupling of the sidechain precursor to the quinazolinedione
core precursor to provide the compounds of the present invention
occurs as described in WO/02 102793, priority date Jun. 19, 2001
and WO/01 53273, priority date Oct. 18, 2000, and references cited
therein.
D. Post-Coupling Transformations
[0725] Coupling of the sidechain precursors to the
aminoquinazolinedione core precursors may give rise directly to
invention compounds. Alternatively, post-coupling transformations
may be necessary to give rise to invention compounds. Typical
post-coupling transformation include deprotection of protected
amines to provide invention compounds of formula II, as depicted in
Scheme III. Deprotection, as well as reaction with acrylonitrile or
the like give rise to invention compounds of formulas III and IV.
##STR387##
Pharmaceutical Formulations
[0726] The present invention also provides pharmaceutical
compositions which comprise a bioactive invention compound or a
salt such or a pharmaceutically acceptable salt thereof and
optionally a pharmaceutically acceptable carrier. The compositions
include those in a form adapted for oral, topical or parenteral use
and can be used for the treatment of bacterial infection in mammals
including humans.
[0727] The compounds, such as antibiotic compounds, also referred
to herein as antimicrobial compounds, according to the invention
can be formulated for administration in any convenient way for use
in human or veterinary medicine, by analogy with other bioactive
agents such as antibiotics. Such methods are known in the art and
are not described in detail herein.
[0728] The composition can be formulated for administration by any
route known in the art, such as subdermal, by-inhalation, oral,
topical or parenteral. The compositions may be in any form known in
the art, including but not limited to tablets, capsules, powders,
granules, lozenges, creams or liquid preparations, such as oral or
sterile parenteral solutions or suspensions.
[0729] The topical formulations of the present invention can be
presented as, for instance, ointments, creams or lotions, eye
ointments and eye or ear drops, impregnated dressings and aerosols,
and may contain appropriate conventional additives such as
preservatives, solvents to assist drug penetration and emollients
in ointments and creams.
[0730] The formulations may also contain compatible conventional
carriers, such as cream or ointment bases and ethanol or oleyl
alcohol for lotions. Such carriers may be present, for example,
from about 1% up to about 98% of the formulation. For example, they
may form up to about 80% of the formulation.
[0731] Tablets and capsules for oral administration may be in unit
dose presentation form, and may contain conventional excipients
such as binding agents, for example syrup, acacia, gelatin,
sorbitol, tragacanth, or polyvinylpyrollidone; fillers, for example
lactose, sugar, maize-starch, calcium phosphate, sorbitol or
glycine; tabletting lubricants, for example magnesium stearate,
talc, polyethylene glycol or silica; disintegrants, for example
potato starch; or acceptable wetting agents such as sodium lauryl
sulphate. The tablets may be coated according to methods will known
in normal pharmaceutical practice.
[0732] Oral liquid preparations may be in the form of, for example,
aqueous or oily suspensions, solutions, emulsions, syrups or
elixirs, or may be presented as a dry product for reconstitution
with water or other suitable vehicle before use. Such liquid
preparations may contain conventional additives, such as suspending
agents, for example sorbitol, methyl cellulose, glucose syrup,
gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium
stearate gel or hydrogenated edible fats, emulsifying agents, for
example lecithin, sorbitan monooleate, or acacia; non-aqueous
vehicles (which may include edible oils), for example almond oil,
oily esters such as glycerine, propylene glycol, or ethyl alcohol;
preservatives, for example methyl or propyl p-hydroxybenzoate or
sorbic acid, and, if desired, conventional flavoring or coloring
agents.
[0733] For parenteral administration, fluid unit dosage forms are
prepared utilizing the compound and a sterile vehicle, water being
preferred. The compound, depending on the vehicle and concentration
used, can be either suspended or dissolved in the vehicle or other
suitable solvent. In preparing solutions, the compound can be
dissolved in water for injection and filter sterilized before
filling into a suitable vial or ampoule and sealing.
Advantageously, agents such as a local anesthetic preservative and
buffering agents can be dissolved in the vehicle. To enhance the
stability, the composition can be frozen after filling into the
vial and the water removed under vacuum. The dry lyophilized powder
is then sealed in the vial and an accompanying vial of water for
injection may be supplied to reconstitute the liquid prior to use.
Parenteral suspensions are prepared in substantially the same
manner except that the compound is suspended in the vehicle instead
of being dissolved and sterilization cannot be accomplished by
filtration. The compound can be sterilized by exposure to ethylene
oxide before suspending in the sterile vehicle. Advantageously, a
surfactant or wetting agent is included in the composition to
facilitate uniform distribution of the compound.
[0734] The compositions may contain, for example, from about 0.1%
by weight, e.g., from about 10-60% by weight, of the active
material, depending on the method of administration. Where the
compositions comprise dosage units, each unit will contain, for
example, from about 50-500 mg of the active ingredient. The dosage
as employed for adult human treatment will range, for example, from
about 100 to 3000 mg per day, for instance 1500 mg per day
depending on the route and frequency of administration. Such a
dosage corresponds to about 1.5 to 50 mg/kg per day. Suitably the
dosage is, for example, from about 5 to 20 mg/kg per day.
Biological Activity
[0735] The invention compounds can be screened to identify
bioactive molecules with different biological activities using
methods available in the art. The bioactive molecules, for example,
can possess activity against a cellular target, including but not
limited to enzymes and receptors, or a microorganism. A target
cellular ligand or microorganism is one that is known or believed
to be of importance in the etiology or progression of a disease.
Examples of disease states for which compounds can be screened for
biological activity include, but are not limited to, inflammation,
infection, hypertension, central nervous system disorders, and
cardiovascular disorders.
[0736] In one embodiment, the invention provides methods of
treating or preventing a bacterial infection in a subject, such as
a human or other animal subject, comprising administering an
effective amount of an invention compound as disclosed herein to
the subject. In one embodiment, the compound is administered in a
pharmaceutically acceptable form optionally in a pharmaceutically
acceptable carrier. As used herein, an "infectious disorder" is any
disorder characterized by the presence of a microbial infection,
such as bacterial infections. Such infectious disorders include,
for example central nervous system infections, external ear
infections, infections of the middle ear, such as acute otitis
media, infections of the cranial sinuses, eye infections,
infections of the oral cavity, such as infections of the teeth,
gums and mucosa, upper respiratory tract infections, lower
respiratory tract infections, genitourinary infections,
gastrointestinal infections, gynecological infections, septicemia,
bone and joint infections, skin and skin structure infections,
bacterial endocarditis, burns, antibacterial prophylaxis of
surgery, and antibacterial prophylaxis in immunosuppressed
patients, such as patients receiving cancer chemotherapy, or organ
transplant patients. The compounds and compositions comprising the
compounds can be administered by routes such as topically, locally
or systemically. Systemic application includes any method of
introducing the compound into the tissues of the body, e.g.,
intrathecal, epidural, intramuscular, transdermal, intravenous,
intraperitoneal, subcutaneous, sublingual, rectal, and oral
administration. The specific dosage of antimicrobial to be
administered, as well as the duration of treatment, may be adjusted
as needed.
[0737] The compounds of the invention may be used for the treatment
or prevention of infectious disorders caused by a variety of
bacterial organisms. Examples include Gram positive and Gram
negative aerobic and anaerobic bacteria, including Staphylococci,
for example S. aureus; Enterococci, for example E. faecalis;
Streptococci, for example S. pneumoniae; Haemophilus, for example
H. influenza; Moraxella, for example M. catarrhalis; and
Escherichia, for example E. coli. Other examples include
Mycobacteria, for example M. tuberculosis; intercellular microbes,
for example Chlamydia and Rickettsiae; and Mycoplasma, for example
M. pneumoniae.
[0738] The ability of a compound of the invention to inhibit
bacterial growth, demonstrate in vivo activity, and enhanced
pharmacokinetics are demonstrated using pharmacological models that
are well known to the art, for example, using models such as the
tests described below.
Test A--Antibacterial Assays
[0739] The compounds of the present invention were tested against
an assortment of Gram-negative and Gram-positive organisms using
standard microtitration techniques (Cohen et. al., Antimicrob.,
1985; 28:766; Heifetz, et. al., Antimicrob., 1974; 6:124). The
results of the evaluation are shown in Tables 1A and B.
TABLE-US-00001 TABLE 1A Minimum Inhibitory Concentrations .mu.g/mL
Gram Negative Bacteria H. influenzae M. catarrhalis E. coli HI-3542
BC-3531 2026 Compound ##STR388## stereoisomeric mixture 2 0.5 8
##STR389## racemic mixture of enantiomers 4 16 32 ##STR390## single
enantiomer 1 2 8 ##STR391## single enantiomer 4 4 32 ##STR392##
single enantiomer 2 4 8 ##STR393## stereoisomeric mixture 8 16 64
##STR394## single enantiomer 0.5 1 4 ##STR395## racemic mixture of
enantiomers 2 4 8 ##STR396## racemic mixture of enantiomers 4 4 8
##STR397## racemic mixture of enantiomers 8 16 32 ##STR398##
stereoisomeric mixture 8 64 64 ##STR399## stereoisomeric mixture 4
16 16 ##STR400## single enantiomer 16 16 64 ##STR401## single
enantiomer 64 64 64 Compound No. or Example No. ##STR402##
stereoisomeric mixture 32 5.25 64 ##STR403## stereoisomeric mixture
32 16 64 ##STR404## stereoisomeric mixture 1 8 2 NT = Not
tested
[0740] TABLE-US-00002 TABLE 1B Minimum Inhibitory Concentrations
.mu.g/mL Gram Positive Bacteria E. faecalis S. pneumo S. aureus S
pyogenes MGH-2 SV-1 UC-76 C203 Compound Structure or Example No.
##STR405## stereoisomeric mixture 0.5 0.125 0.25 0.125 ##STR406##
racemic mixture of enantiomers 4 0.5 1 0.5 ##STR407## single
enantiomer 0.25 0.06 0.125 0.03 ##STR408## single enantiomer 0.5
0.125 0.25 0.125 ##STR409## single enantiomer 1 0.125 0.5 0.25
##STR410## stereoisomeric mixture 2 0.5 2 0.5 ##STR411## single
enantiomer 0.125 0.015 0.06 0.03 Compound Structure ##STR412##
single enantiomer 0.5 0.06 0.25 0.06 ##STR413## single enantiomer
0.5 0.125 0.25 0.125 ##STR414## racemic mixture of enantiomers 4 1
2 1 ##STR415## stereoisomeric mixture 4 0.5 1 1 ##STR416##
stereoisomeric mixture 32 8 8 8 ##STR417## single enantiomer 1
0.125 0.25 0.125 ##STR418## single enantiomer 2 0.25 1 0.5
##STR419## stereoisomeric mixture 32 32 12 32 ##STR420##
stereoisomeric mixture 16 8 8 16 ##STR421## stereoisomeric mixture
1 0.06 0.25 0.06
[0741] The following examples are provided to illustrate but not
limit the claimed invention.
A. Synthesis of Sidechain Precursors
EXAMPLE 1
Preparation of (2-Cyano-1-pyrrolidin-3-yl-ethyl)-carbamic acid
tert-butyl ester
[0742] ##STR422##
A. 3-(2-Cyano-vinyl)-pyrrolidine-1-carboxylic acid benzyl ester
[0743] ##STR423##
[0744] A solution of 3-formyl-pyrrolidine-1-carboxylic acid benzyl
ester (2.25 g, 9.65 mmol), cyanomethyl-phosphonic acid diethyl
ester (1.88 g, 10.6 mmol) and cesium carbonate (3.46 g, 10.6 mmol)
in dry THF (100 mL) was heated at 50.degree. C. for 3 hours. The
solvent was removed in vacuo. The crude residue was taken up in
ethyl acetate (100 mL) and washed with saturated NH.sub.4Cl (100
mL), brine (100 mL), dried with MgSO.sub.4 and concentrated in
vacuo. The crude residue was purified on a 40 g silica gel column
(0 to 60% ethyl acetate in hexanes) to give 2.22 g of the title
compound as a mixture of E and Z isomers (yield: 90%). MS (APCI+):
m/z 257 (M+H).sup.+. B.
3-(1-tert-Butoxycarbonylamino-2-cyano-ethyl)-pyrrolidine-1-carboxylic
acid benzyl ester ##STR424##
[0745] To a solution of 3-(2-cyano-vinyl)-pyrrolidine-1-carboxylic
acid benzyl ester (8.24 g, 32.1 mmol) in absolute ethanol (100 mL)
was added ammonia (ca. 5 mL) and the solution was heated in a
sealed reactor at 80-100.degree. C. for 3 days. The solution was
concentrated in vacuo. The resulting amine was dissolved in THF
(100 mL), Boc anhydride (8.76 g, 40.2 mmol) was added, and the
solution was stirred at room temperature for 18 hours. The solution
was concentrated in vacuo. The residue was taken up in ethyl
acetate (100 mL), washed with saturated aqueous NH.sub.4Cl (100 mL)
and brine (100 mL), dried with MgSO.sub.4 and concentrated in
vacuo. The crude product was purified on a 330 g silica gel column
(10 to 50% ethyl acetate in hexanes) to give 9.28 g of the title
compound as a 1:1 mixture of diastereomers (yield: 77%). MS
(APCI+): m/z 274 (M+H-Boc).sup.+.
C. (2-Cyano-1-pyrrolidin-3-yl-ethyl)-carbamic acid tert-butyl
ester
[0746] ##STR425##
[0747] A solution of
3-(1-tert-butoxycarbonylamino-2-cyano-ethyl)-pyrrolidine-1-carboxylic
acid benzyl ester (2.00 g, 5.36 mmol) and ammonium formate (1.00 g,
16.1 mmol) in methanol (50 mL) was purged with nitrogen and then
10% Pd/C (0.5 g) was added. The mixture was stoppered and stirred
at room temperature for 17 hours. The solution was filtered through
Celite and solids were rinsed with methanol. The filtrate was
concentrated in vacuo to give 1.25 g of the title compound (yield:
97%). MS (APCI+): m/z 240 (M+H).sup.+.
EXAMPLE 2
Preparation of
N-(1-Azetidin-3-yl-cyclopropyl)-2,2,2-trifluoro-acetamide
[0748] ##STR426##
A. 1-(1-Benzhydryl-azetidin-3-yl)-cyclopropylamine
[0749] ##STR427##
[0750] See Chem. Rev., 1979, Vol. 79, No. 4; Tet. Lett. 44, 2003,
2485
[0751] To a solution of 1-benzhydryl-azetidine-3-carbonitrile (10
g) in THF (200 mL) were added successively at room temperature
titanium isopropoxide (Ti(OiPr).sub.4) (1 equivalent) and
ethylmagnesium bromide (2.2 equivalents). The resulting reaction
mixture was stirred for 30 minutes. Boron trifluoride diethyl
etherate (BF.sub.3OEt.sub.2)(2 equivalents) was then added.
Stirring was continued for a period of 30 minutes. A solution of
10% sodium hydroxide was added, and the mixture was extracted three
times with ethyl acetate (EtOAc). The combined ethyl acetate layers
were dried over Na.sub.2SO.sub.4, and concentrated. The crude
material was purified by chromatography (EtOAc to 7:3 EtOAc:EtOH)
to yield the title compound as a yellow solid (4.96 g, 44% yield).
MS (APCI+): m/z 279 (M+H).sup.+.
B.
N-[1-(1-Benzhydryl-azetidin-3-yl)-cyclopropyl]-2,2,2-trifluoro-acetamid-
e
[0752] ##STR428##
[0753] See J. Med Chem. 1993, Vol. 36, No. 7
[0754] To a stirred solution of
1-(1-benzhydryl-azetidin-3-yl)-cyclopropylamine (2.5 g) in
chloroform (60 mL) was added a solution of trifluoroacetic
anhydride (1.25 equivalents) in chloroform (30 mL) dropwise at room
temperature. The reaction was stirred for two hours, then washed
with 10% NaHCO.sub.3, and subsequently brine. The solution was then
concentrated and purified by chromatography (gradient: 3:1
hexanes:EtOAc to EtOAc) yielding 0.57 g (17% yield) of the title
compound. MS(APCI+): m/z 375 (M+H).sup.+.
C. N-(1-Azetidin-3-yl-cyclopropyl)-2,2,2-trifluoro-acetamide
[0755] ##STR429##
[0756] To
N-[1-(1-benzhydryl-azetidin-3-yl)-cyclopropyl]-2,2,2-trifluoro--
acetamide in methanol was added 10% Pd/C (20%) and hydrochloric
acid (1 equivalent). The resulting mixture was stirred under an
atmosphere of hydrogen gas overnight. The mixture was then filtered
through a pad of celite and the filtrate was concentrated to yield
a mixture of the azetidinium hydrochloride and diphenylmethane
(0.56 g, 90% yield). The crude mixture was taken on to the next
reaction without purification, MS(APCI+): m/z 209 (M+H).sup.+.
EXAMPLE 3
Preparation of
N-(3-Ethyl-azetidin-3-ylmethyl)-2,2,2-trifluoro-acetamide
[0757] ##STR430##
A. 1-Benzhydryl-3-ethyl-azetidin-3-ol
[0758] ##STR431##
[0759] To a solution of 1-benzhydryl-azetidin-3-one (10 g) in
diethylether (200 mL) cooled to 0.degree. C. with an ice bath was
added dropwise a solution of ethylmagnesium bromide in ether (3.0
M, 2 equivalents). The reaction was allowed to stir at 0.degree. C.
until the bath warmed and then reacted at room temperature for
three days. The reaction was quenched with aqueous ammonium
chloride and then extracted three times with EtOAc. The organic
extract washed with brine, dried, and then concentrated. The
product was purified by flash chromatography (2:1 hexanes:EtOAc) to
give the title compound (6.33 g, 56%), MS (APCI+): m/z 268
(M+H).sup.+.
B. Methanesulfonic acid 1-benzhydryl-3-ethyl-azetidin-3-yl
ester
[0760] ##STR432##
[0761] To a cooled (0.degree. C.) solution of the
1-benzhydryl-3-ethyl-azetidin-3-ol (6.33 g) and triethylamine (1.3
equivalents) in dichloromethane (100 mL) was added a solution of
methanesulfonyl chloride (1.3 equivalents) in dichloromethane (30
mL) dropwise. As soon as all of the methanesulfonyl chloride had
been added, the cooling bath was removed, and the reaction was
allowed to stir at room temperature for 1 hour. The solution was
then diluted with more dichloromethane and washed with water two
times. The organic solution was then dried and concentrated (8.01
g, 98% yield). The crude material was used in the next step without
further purification.
C. 1-Benzhydryl-3-ethyl-azetidine-3-carbonitrile
[0762] ##STR433##
[0763] To a solution of methanesulfonic acid
1-benzhydryl-3-ethyl-azetidin-3-yl ester (8.01 g) in
dimethylformamide (DMP) (120 mL) at room temperature was added
sodium cyanide (2.5 equivalents) in water (40 mL) dropwise. The
solution was then heated to 60.degree. C. and stirred overnight The
solution was then diluted with 500 mL water and the precipitate was
extracted into EtOAc 3 times. The organic extract washed with water
2 times and then dried over Na.sub.2SO.sub.4 and concentrated in
vacuo. The product was purified by chromatography (gradient: 9:1
hex:EtOAc to EtOAc) to give the title compound (5.50 g, 86% yield),
MS (APCI+): m/z 277 (M+H).sup.+.
D. C-(1-Benzhydryl-3-ethyl-azetidin-3-yl)-methylamine
[0764] ##STR434##
[0765] To a solution of
1-benzhydryl-3-ethyl-azetidine-3-carbonitrile (5.50 g) in THF (60
mL) was added LAH (3.5 equivalents) in THF (1 M) slowly. The
solution was refluxed for 2 hours. The reaction was then cooled to
room temperature and 100 mL diethylether was added followed by 2.8
mL water then 2.8 mL 10% NaOH then 5.6 mL water. After 30 minutes
of vigorous stirring the mixture was filtered. The aluminum salts
were washed 5 times with THF. The combined organic filtrates were
dried, and concentrated. The crude product was used in the next
step without further purification. 5.16 g, 92% yield, MS (APCI+):
m/z 281 (M+H).sup.+.
E.
N-(1-Benzhydryl-3-ethyl-azetidin-3-ylmethyl)-2,2,2-trifluoro-acetamide
[0766] ##STR435##
[0767] To a stirred solution of
C-(1-benzhydryl-3-ethyl-azetidin-3-yl)-methylamine (5.16 g) in
chloroform (120 mL) was added a solution of trifluoroacetic
anhydride (1.25 equivalents) in chloroform (60 mL) dropwise at room
temperature. The reaction was stirred for two hours, then washed
with 10% NaHCO.sub.3, then brine. The solution was then dried, then
concentrated and purified by chromatography (3:1 hexanes:EtOAc to
EtOAc) to provide the title compound (3.67 g, 53% yield), MS
(APCI+): m/z 377.3 (M+H).sup.+.
F. N-(3-Ethyl-azetidin-3-ylmethyl)-2,2,2-trifluoro-acetamide
[0768] ##STR436##
[0769]
N-(1-Benzhydryl-3-ethyl-azetidin-3-ylmethyl)-2,2,2-trifluoro-aceta-
mide (3.67 g) was hydrogenated (Pd/C in 100 mL MeOH) with one
equivalent of HCl overnight to give 2.40 g, (100% yield) of the
title compound which was used without purification. MS (APCI+): m/z
211 (M+H).sup.+.
EXAMPLE 4
Preparation of N-(1-Azetidin-3-yl-propyl)-2,2,2-trifluoroacetamide
hydrochloride
[0770] ##STR437##
A. 1-Benzhydryl-azetidine-3-carboxylic acid
[0771] ##STR438##
[0772] A suspension of 1-benzhydryl-azetidine-3-carbonitrile (2.09
g, 8.42 mmol) in concentrated hydrochloric acid (12 M, 15 mL) was
heated at reflux for 30 minutes. The resulting solution was cooled
to 0.degree. C., and 6 M sodium hydroxide was added until the
mixture reached a pH of about 7. The aqueous mixture was then
extracted with dichloromethane (3.times.150 mL) and
dichloromethane:methanol (10:1, 3.times.150 mL). The combined
organic layers were dried, filtered, and concentrated under reduced
pressure to give the title compound (1.60 g, 71% yield). MS (APCI):
m/z 268 (M+H).sup.+.
B. 1-Benzhydryl-azetidine-3-carboxylic acid methoxymethylamide
[0773] ##STR439##
[0774] 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride (8.0 g, 42 mmol) was added to a suspension of
1-benzhydryl-azetidine-3-carboxylic acid (7.42 g, 27.8 mmol),
N,O-dimethyl-hydroxyl-amine hydrochloride (4.24 g, 43.5 mmol), and
triethylamine (11.6 mL, 83.3 mmol) in dichloromethane (150 mL). The
suspension was then stirred at room temperature for 60 minutes. The
suspension was diluted with dichloromethane (300 mL), and the
resulting solution washed with water (3.times.100 mL). The organic
layer was then dried (magnesium sulfate), filtered, and
concentrated under reduced pressure. The resulting solid was
purified via medium pressure liquid chromatography eluting with
dichloromethane:methanol (40:1) to deliver 4.76 g (55% yield) of
the title compound as a white solid (mp 103-106.degree. C.); MS
(APCI+): m/z 311 (M+H).sup.+.
C. 1-(1-Benzhydryl-azetidin-3-yl)-propan-1-one
[0775] ##STR440##
[0776] A solution of ethylmagnesium bromide in tetrahydrofuran (1.0
M, 32.5 mL) was add to a solution of
1-benzhydryl-azetidine-3-carboxylic acid methoxymethylamide (3.36
g, 10.8 mmol) at -70.degree. C. in tetrahydrofuran (60 mL). The
resulting reaction mixture was then stirred at 0.degree. C. for 1
hour. The reaction was then poured into a saturated aqueous
solution of ammonium chloride (75 mL) at 0.degree. C. The mixture
was then extracted with diethyl ether (300 mL); the aqueous layer
was then extracted again with diethyl ether (2.times.100 mL). The
combined organic layers were dried over magnesium sulfate,
filtered, and concentrated under reduced pressure. The crude
product was purified via medium pressure chromatography eluting
with dichloromethane:methanol (40:1) to afford 2.69 g (89% yield)
of the title compound as a waxy yellow solid (mp 73-75.degree. C.);
MS (APCI+): m/z 280 (M+H).sup.+.
D.
N-[1-(1-Benzhydryl-azetidin-3-yl)propyl]-2,2,2-trifluoroacetamide
[0777] ##STR441##
[0778] Ammonium acetate (6.00 g, 77.8 mmol) was added to a mixture
of 1-(1-benzhydryl-azetidin-3-yl)-propan-1-one (2.59 g, 9.27 mmol)
and 4 angstrom molecular sieves (2.60 g) in methanol (80 mL). The
mixture was cooled to 0.degree. C., and sodium cyanoborohydride
(1.17 g, 18.5 mmol) was added in several portions. The mixture was
then stirred at room temperature for 22 hours. The suspension was
filtered, and filtrate was concentrated under reduced pressure. The
resulting residue was partially dissolved in dichloromethane (500
mL). The mixture was then washed with saturated aqueous sodium
carbonate (100 mL). The layers were separated, and the aqueous
layer was extracted with dichloromethane (100 mL). The combined
organic layers were dried over magnesium sulfate, filtered, and
concentrated under reduced pressure to give 2.59 g of a clear oil
which was used without further purification.
[0779] A solution of the crude diamine (2.59 g) and triethylamine
(3.86 mL, 27.7 mmol) in dichloromethane (60 mL) at 0.degree. C. was
treated with trifluoroacetic anhydride (1.06 mL, 13.9 mmol). The
resulting solution was then stirred at room temperature for 45
minutes. After 45 minutes, an additional amount of trifluoroacetic
anhydride (350 .mu.L) was added, and stirring continued for 15
minutes at room temperature. The solution was cooled to 0.degree.
C., and saturated aqueous sodium bicarbonate (10 mL) was added. The
mixture was then partitioned between dichloro-methane (300 mL) and
saturated aqueous bicarbonate (40 mL). The layers were separated;
the organic layer washed with water (50 mL), dried over magnesium
sulfate, filtered, and concentrated under reduced pressure. The
resulting oil was purified via medium pressure liquid
chromatography eluting with a gradient of hexanes:ethyl acetate
(80:20 to 60:40) to give 1.84 g (53% yield) of the title compound.
MS (APCI+) m/z 377 (M+H).sup.+.
E. N-(1-Azetidin-3-yl-propyl)-2,2,2-trifluoroacetamide
hydrochloride
[0780] ##STR442##
[0781] A mixture of
N-[1-(1-benzhydryl-azetidin-3-yl)propyl]-2,2,2-trifluoroacetamide
(1.72 g, 4.57 mmol), 10% Pd/C (2.02 g), concentrated hydrochloric
acid (12.0 M, 0.380 mL) in methanol (60 mL) was hydrogenated at 50
psi for 6 hours. An additional amount of 10% Pd/C (1.5 g) was
added, and the hydrogenation continued for 22 hours. The solvent
was removed under reduced pressure to deliver a yellow residue. The
residue was then concentrated several times with toluene and then
dried in vacuo at 50.degree. C. for several hours to deliver the
title compound contaminated with diphenylmethane. The crude
material was triturated with hexanes to provide 1.13 g, (100%
yield) of the title compound. MS (APCI+): m/z 211 (M+H).sup.+.
EXAMPLE 5
Preparation of
2,2,2-Trifluoro-N-(3-methyl-azetidin-3-ylmethyl)-acetamide
hydrochloride
[0782] ##STR443##
[0783] A mixture of
N-(1-Benzhydryl-3-methyl-azetidin-3-ylmethyl)-2,2,2-trifluoro-acetamide
(3.19 g, 8.80 mmol), 10% Pd/C (2.5 g), concentrated hydrochloric
acid (12 M, 0.732 mL) in methanol (50 mL) was hydrogenated at 50
psi for 8 hours. The solvent was removed under reduced pressure to
deliver a yellow residue. The residue was then concentrated several
times with toluene. The resulting solid was then triturated with
hexanes, and the supernatant was discarded. The resulting white
solid was dried in vacuo to provide 1.91 g (93% yield) of the title
compound. MS (APCI+): m/z 197 (M+H).sup.+.
EXAMPLE 6
Preparation of (R) and (S)-1-Pyrrolidin-3-yl-cyclopropylamine
[0784] ##STR444##
A. N,N-Dibenzylacrylamide
[0785] ##STR445##
[0786] A round bottom flask was charged with tetrahydrofuran (3750
mL) and cooled to -78.degree. C. under nitrogen. Acryloyl chloride
(55.7 g, 48.9 mL, 0.615 mol) and diisopropylethylamine (87.3 g, 118
mL, 0.676 mol) were added followed by the slow addition (over a
period of 20 minutes) of dibenzylamine (109.6 g, 106 mL, 0.555
mol). The reaction mixture was allowed to warm up to room
temperature and stirred at room temperature for 1.0 hour. A large
quantity of white precipitate was observed and thin layer
chromatography indicated the reaction was complete. The solids were
removed by filtration and the filtrate was concentrated under
vacuum to afford a quantitative yield of the title compound.
B. N-(Trimethylsilylmethyl)-.alpha.-methylbenzylamine
[0787] ##STR446##
[0788] A mixture of (S)-(-)-.alpha.-methylbenzylamine (100 g, 106.4
mL, 0.82 mol), chloromethyltrimethylsilane (115.1 mL, 101.2 g, 0.82
mol), and triethylamine (126.5 mL, 96.2 g, 0.95 mol) was heated at
reflux for 24 hours until LCMS indicated the reaction was complete.
The reaction mixture was triturated with heptane and the HCl salt
was filtered off. The heptane filtrate was concentrated to an oily
residue which was distilled under vacuum (42-50.degree. C./0.4-0.7
mmHg) to furnish 67.8 g (40% yield) of the title compound.
C.
N-(Methoxymethyl)-N-(trimethylsilylmethyl)-.alpha.-methylbenzylamine
[0789] ##STR447##
[0790] To a stirred solution of aqueous formaldehyde (37%, 152.1 g,
1.9 mol) at 0.degree. C. was added the
N-(trimethylsilylmethyl)-.alpha.-methylbenzylamine from the
previous step (310 g, 1.5 mol) over a period of 0.5 hour followed
by the addition of methanol (100 mL) and potassium carbonate (200
g). The reaction mixture was stirred at 0-10.degree. C. for 1-2
hours. The mixture was filtered and the filtrate was extracted with
diethyl ether (1 time). The ether layer was dried with sodium
sulfate and concentrated to an oil which was distilled using a
Kugelrohl apparatus to furnish 210 g (56%) of the title
compound.
D. 1-(1-Phenyl ethyl)-pyrrolidine-3-carboxylic acid
dibenzylamide
[0791] ##STR448##
[0792] N,N-Dibenzylacrylamide (79.5 g, 0.317 mol) and
N-(methoxymethyl)-N-(trimethylsilylmethyl)-.alpha.-methylbenzylmine
(103 g, 0.412 mol) were dissolved in CH.sub.2Cl.sub.2 (1500 mL) and
cooled to 0.degree. C. Trifluoroacetic acid solution (1.0 M in
CH.sub.2Cl.sub.2, 27 mL) was added over a period of 20 minutes and
the resulting reaction mixture was stirred at room temperature
overnight. The mixture washed with aqueous NaHCO.sub.3, brine,
dried over Na.sub.2SO.sub.4 and concentrated. The residue was
purified by flash chromatography (heptane-EtOAc-Et.sub.3N/10:2:0.1)
to furnish 97.7 g of the title compound (77% yield) as a mixture of
two diasteromers.
E.
Dibenzyl-{1-[1-(1-phenyl-ethyl)-pyrrolidin-3-yl]-cyclopropyl}-amine
[0793] ##STR449##
[0794] To a round bottom flask charged with tetrahydrofuran (1400
mL) was added ethylmagnesium bromide (EtMgBr) (3.0 M in Et.sub.2O,
178 mL, 0.534 mol) at -78.degree. C. A solution of Ti(OiPr).sub.4
(64.8 g, 66.0 mL, 0.228 mol) in THF (150 mL) was added then added
at a rate to maintain the temperature below -68.degree. C. The dark
solution was allowed to stir at -68.degree. C. for 3 minutes before
a solution of 1-(1-phenyl-ethyl)-pyrrolidine-3-carboxylic acid
dibenzylamide (86.6 g, 0.218 mol) in THP (150 mL) was added below
-68.degree. C. The reaction mixture was allowed to warm to room
temperature, and then was stirred at room temperature for 1.0 hour
and then was heated at reflux for 1.0 hour. The reaction mixture
was then cooled to 8.degree. C. EtMgBr (3.0 M in ether, 150 mL,
0.450 mol) was added followed by the rapid addition of
Ti(OiPr).sub.4 (54.6 g, 55.6 mL, 0.192 mol) in THF (150 mL). The
resulting mixture was stirred at room temperature for 1.0 hour
before it was quenched with aqueous ammonium chloride (3000 mL) and
water (800 mL). The mixture was filtered through Celite, rinsed
with ether. The organic layer was separated. The aqueous layer was
made basic (pH.about.8.5) with aqueous NaOH and extracted with
ether. The combined organic layers were dried over
Na.sub.2SO.sub.4, concentrated and purified by flash chromatograph
(heptane-EtOa\Ac-Et.sub.3N/10:1:0.1) to provide the title compound
as a mixture of stereoisomers, which were separated prior to
subsequent transformations. Isomer 1 (31.3 g, 35%) as colorless
crystals (mp 76-76.5.degree. C.). The stereochemical structure of
isomer 1 was confirmed by a single crystal X-ray diffraction
experiment.
[0795] Isomer 2: The impure oil (18 g) from the above purification
was further chromatographed with heptane/methylbutyl ether
(MTBE)/Et.sub.3N (100:0.5:0.5) to furnish 11 g of isomer 2 which
was about 90% pure as a colorless oil. This oil was dissolved in
Et.sub.2O (350 mL) and titrated with 2.0 M Et.sub.2O--HCl (12.8
mL). The resulting white solid was collected by filtration, rinsed
with ether, dissolved in MeOH, neutralized with 15% NaOH, extracted
with ether (2 times), washed with brine, dried over
Na.sub.2SO.sub.4, concentrated under vacuum to afford a thick oil
which was recrystallized in EtOH at -30.degree. C. to furnish 10.1
g of the title compound (22% yield) as colorless crystals (mp
61-61.3.degree. C.).
F. S-1-Pyrrolidin-3-yl-cyclopropylamine
[0796] ##STR450##
[0797]
Dibenzyl-{1-[1-(1-phenyl-ethyl)-pyrrolidin-3-yl]-cyclopropyl}-amin-
e (3.00 g, 7.32 mmol) was charged with 20% Pd/C and subjected to 50
psi hydrogenation conditions. After 48 hours the reaction was
filtered and concentrated to give 764 mg of the title compound.
(yield: 83%). MS (APCI+): m/z 127 (M+H).sup.+.
G. (R)-1-Pyrrolidin-3-yl-cyclopropylamine
[0798] ##STR451##
[0799]
Dibenzyl-{1-[1-(1-phenyl-ethyl)-pyrrolidin-3-yl]-cyclopropyl}-amin-
e (3.01 g, 7.32 mmol) was charged with 20% Pd/C and subjected to 50
psi hydrogenation conditions. After 48 hours the reaction was
filtered and concentrated to give 844 mg of the title compound.
(yield: 91%). MS (APCI+): m/z 127 (M+H).sup.+.
EXAMPLE 7
Preparation of Pyrrolidin-3-ylmethyl-carbamic acid tert-butyl
ester
A. (S)-Methanesulfonic acid 1-benzyl-pyrrolidin-3-yl ester
[0800] ##STR452##
[0801] 1-Benzyl-pyrrolidin-3-ol (Synthetic Communications, 1985)
(25.01 g, 141 mmol) was taken up in dichloromethane and charged
with triethylamine (29 mL). The resulting solution was cooled to
0.degree. C. and charged with mesyl chloride (13.1 mL). After 14
hours the reaction washed with saturated sodium bicarbonate
followed with water and brine. The organic layer was dried and
concentrated to give the title compound (30.2 g, 84% yield). MS
(APCI+): m/z 256 (M+H).sup.+.
B. (R)-1-Benzyl-pyrrolidine-3-carbonitrile
[0802] ##STR453##
[0803] (R)-1-Benzyl-pyrrolidine-3-carbonitrile (29.8 g, 117 mmol)
was taken up in acetonitrile and charged with sodium cyanide (20.2
g, 412 mmol) and tetra butyl ammonium cyanide (3.11 g, 11.6 mmol)
then heated to reflux. After 48 hours the reaction was diluted with
ethyl acetate and washed with saturated sodium bicarbonate, water
and brine. The organic layer was dried, concentrated and purified
via column chromatography (3:1 hexanes/ethyl acetate) leaving 15.4
g of the title compound (71% yield). MS (APCI+): m/z 187
(M+H).sup.+.
C. (R) --C-(1-Benzyl-pyrrolidin-3-yl)-methylamine
[0804] ##STR454##
[0805] 1-Benzyl-pyrrolidine-3-carbonitrile (5.08 g, 27.3 mmol) was
taken up in THF and cooled to 0.degree. C. After 10 minutes LAH
(2.09 g, 55.1 mmol) in THF at 0.degree. C. was slowly added to the
pyrrolidine solution. Gas evolution was observed, and the reaction
was allowed to continue at 0.degree. C. for 30 minutes. The
reaction was allowed to warm to room temperature and stirred for 2
additional hours. The reaction was quenched with water (2 mL), 1N
NaOH (2 mL), and again water (6 mL). The resulting slurry was
filtered over a pad of celite which washed with dichloromethane and
the combined filtrates were concentrated to give 4.2 g of the title
compound (yield: 82%). MS (APCI+): m/z 191 (M+H).sup.+.
D. (R)-(1-Benzyl-pyrrolidin-3-ylmethyl)-carbamic acid tert-butyl
ester
[0806] ##STR455##
[0807] R-C-(1-Benzyl-pyrrolidin-3-yl)-methylamine (2.033 g, 10.7
mmol) was taken up in THF and charged with boc anhydride (6.787 g,
31 mmol). The resulting solution was heated gently to 46.degree. C.
After 6 hours the resulting solution was cooled to room temperature
and concentrated. The crude residue was taken up in dichloromethane
and washed with 1.0 N HCl. The organic washes were purified via
chromatography (0-10% MeOH/CH.sub.2Cl.sub.2) to provide 2.4 g of
the title compound (yield: 76%). MS (APCI+): m/z 291
(M+H).sup.+.
E. Pyrrolidin-3-ylmethyl-carbamic acid tert-butyl ester
[0808] ##STR456##
[0809] (R)-(1-Benzyl-pyrrolidin-3-ylmethyl)-carbamic acid
tert-butyl ester (1.00 g, 3.44 mmol) was charged with 20% Pd/C and
hydrogenated at 50 psi. After 48 hours, the reaction was filtered
and concentrated to give 511 mg of the title compound (yield: 74%).
MS (APCI+): m/z 201 (M+H).sup.+.
EXAMPLE 8
Preparation of Pyrrolidin-3-ylmethyl-carbamic acid tert-butyl
ester
A. [1-(1-Phenyl-ethyl)-pyrrolidin-3-yl]-methanol
[0810] ##STR457##
[0811] 5-Oxo-1-(1-phenyl-ethyl)-pyrrolidine-3-carboxylic acid
methyl ester (Journal of Heterocyclic Chemistry, 1992) (10.0 g,
40.5 mmol) was taken up in diethyl ether and added slowly to a
slurry of LAH (2.31 g, 60.86 mmol) in diethyl ether. The resulting
solution was heated at reflux for 4 hours. The reaction was cooled
to room temperature and quenched with a water/ether mixture. The
resulting solution was allowed to stir for 1 additional hour at
room temperature. The slurry was filtered and washed with
dichloromethane. The filtrates were concentrated at reduced
pressure to give 7.76 g of the title compound (yield: 94%). MS
(APCI+): m/z 206 (M+H).sup.+.
B.
2-[1-(1-Phenyl-ethyl)-pyrrolidin-3-ylmethyl]-isoindole-1,3-dione
[0812] ##STR458##
[0813] [1-(1-Phenyl-ethyl)-pyrrolidin-3-yl]-methanol (4.4 g, 21.5
mmol) was taken up in THF and charged with triphenyl phosphine
(6.27 g, 23.9 mmol), and phthalimide (3.61 g, 24.6 mmol) followed
by diisopropylazodicarboxylate (DIAD) (5.08 g, 25.1 mmol) dropwise.
After 4 hours the reaction was concentrated and the resulting oil
was chromatographed (1-10% isopropyl alcohol/dichloromethane) to
provide 5.6 g of the title compound (yield: 77%). MS (APCI+): m/z
335 (M+H).sup.+.
C. C-[1-(1-Phenyl-ethyl)-pyrrolidin-3-yl]-methylamine
[0814] ##STR459##
[0815] The phthalimide (5.00 g, 14.9 mmol) was taken up in
isopropyl alcohol and charged with hydrazine hydrate (7.04 g, 149
mmol). The resulting solution was heated to 60.degree. C. After 1
hour a colorless precipitate had formed. The reaction was diluted
with isopropyl alcohol and filtered. The filter cake washed with
isopropyl alcohol and the combined filtrates were concentrated to
give an off white oily solid. This residue was partitioned between
water and 1:3 dichloromethane:ether and the organic layer washed
with water then dried over sodium sulfate to give 1.68 g of the
title compound (yield: 55%): MS (APCI+): m/z 205 (M+H).sup.+.
D. [1-(1-Phenyl-ethyl)-pyrrolidin-3-ylmethyl]-carbamic acid
tert-butyl ester
[0816] ##STR460##
[0817] C-[1-(1-Phenyl-ethyl)-pyrrolidin-3-yl]-methylamine (4.01 g,
19.6 mmol) was taken up in THF and charged with boc anhydride (15.3
g, 70.1 mmol). The resulting solution was heated gently to
50.degree. C. After 6 hours the resulting solution was cooled to
room temperature and concentrated. The crude was taken up in
dichloromethane and washed with 1N HCl. The organics were
concentrated to provide the title compound 3.4 g (yield: 58%). MS
(APCI+): m/z 305 (M+H).sup.+.
E. Pyrrolidin-3-ylmethyl-carbamic acid tert-butyl ester
[0818] ##STR461##
[0819] [1-(1-Phenyl-ethyl)-pyrrolidin-3-ylmethyl]-carbamic acid
tert-butyl ester (3.50 g, 11.5 mmol) was taken up in methanol and
charged with 20% Pd/C then subjected to 50 psi hydrogenation
conditions. After 24 hours the reaction was filtered and
concentrated leaving 1.75 g of title compound (yield: 76%). MS
(APCI+): m/z 201 (M+H).sup.+.
EXAMPLE 9
Preparation of C-Oxazol-2-yl-C-pyrrolidin-3-yl-methylamine
[0820] ##STR462##
A. 3-(Hydroxy-oxazol-2-yl-methyl)-pyrrolidine-1-carboxylic acid
benzyl ester
[0821] ##STR463##
[0822] To a solution of oxazole (2.0 g, 29 mmol) in tetrahydrofuran
(30 mL) was added borane-tetrahydrofuran complex (32 mL, 1M in THF)
dropwise at room temperature. The reaction mixture was cooled to
-78.degree. C. and tert-butyllithium (19 mL, 1.7 M in hexanes) was
added dropwise. After stirring for 30 minutes, a solution of
3-formyl-pyrrolidine-1-carboxylic acid benzyl ester (2.0 g, 29
mmol) in tetrahydrofuran (5 mL) was added. The reaction mixture was
stirred at -78.degree. C. for 5 h, then 5% acetic acid in ethanol
(180 mL) was added. The mixture was warmed to room temperature,
poured into brine and extracted three times with ethyl acetate. The
combined organic layers were dried over magnesium sulfate, filtered
and concentrated in vacuo. The crude residue was purified by flash
column chromatography (40% to 100% ethyl acetate in hexanes) to
afford the title compound (4.9 g, 56%). MS (APCI+): m/z 303
(M+H).sup.+.
B. 3-(Azido-oxazol-2-yl-methyl)-pyrrolidine-1-carboxylic acid
benzyl ester
[0823] ##STR464##
[0824] To a cooled (0.degree. C.) solution of
3-(hydroxy-oxazol-2-yl-methyl)-pyrrolidine-1-carboxylic acid benzyl
ester (4.9 g, 16 mmol) in dichloromethane (80 mL) was added
triethylamine (2.9 mL, 21 mmol), followed by methanesulfonyl
chloride (1.51 mL, 19.4 mmol). The solution was warmed to room
temperature and stirred overnight. Dichloromethane was added, and
the solution washed with saturated aqueous sodium chloride. The
organic layer was dried over magnesium sulfate, filtered, and
concentrated. The resulting mesylate was used in the next step
without further purification.
[0825] To a solution of the crude mesylate in N,N-dimethylformamide
(80 mL) was added sodium azide (10 g, 160 mmol): The resulting
mixture was heated at 80.degree. C. overnight. The reaction mixture
was cooled to room temperature, poured into water, and extracted
with ethyl acetate. The organic layer was dried over magnesium
sulfate, filtered, and concentrated in vacuo. The crude residue was
purified by flash column chromatography (0 to 40% ethyl acetate in
hexanes) to afford the title compound (4.9 g, 94%) as a colorless
oil. MS (APCI+): m/z 328 (M+H).sup.+.
C. 3-(Amino-oxazol-2-yl-methyl)-pyrrolidine-1-carboxylic acid
benzyl ester
[0826] ##STR465##
[0827] To a solution of
3-(azido-oxazol-2-yl-methyl)-pyrrolidine-1-carboxylic acid benzyl
ester (1.0 g, 3.1 mmol) in tetrahydrofuran (20 mL) was added
triphenylphosphine (1.85 g, 7.03 mmol) and water (0.60 mL, 31
mmol), and the mixture was allowed to stir at 50.degree. C. for 18
hours. The reaction mixture was cooled to room temperature and
concentrated in vacuo. The resulting residue was purified by flash
chromatography (1:9 methanol/dichloromethane) to afford the title
compound (0.66 g, 71%). .sup.1H NMR (400 M, CDCl.sub.3) .delta.
7.64-7.01 (m, 7H), 5.19-5.08 (m, 2H), 4.01-3.12 (m, 5H), 2.74-2.53
(m, 1H), 2.21-1.55 (m, 4H).
D. C-Oxazol-2-yl-C-pyrrolidin-3-yl-methylamine
[0828] ##STR466##
[0829] To a solution of
3-(Amino-oxazol-2-yl-methyl)-pyrrolidine-1-carboxylic acid benzyl
ester (0.65 g, 2.2 mmol) in methanol (10 mL) was added ammonium
formate (0.68 g, 11 mmol) and 10% palladium on carbon (0.70, 0.65
mmol). The reaction mixture was heated at 65.degree. C. for 2.5
hours, cooled to room temperature, and filtered. The filtrate was
concentrated in vacuo to afford the title compound (0.36 g, 100%).
.sup.1H NMR (400 M}, CDCl.sub.3) .delta. 7.95 (s, 1H), 7.14 (s,
1H), 4.04-3.92 (m, 1H), 3.39-2.58 (m, 7H), 2.18-1.51 (m, 3H).
EXAMPLE 10
Preparation of (2-Cyano-1-pyrrolidin-3-yl-ethyl)-carbamic acid
tert-butyl ester
[0830] ##STR467##
A.
3-(1-tert-Butoxycarbonylamino-2-cyano-ethyl)-pyrrolidine-1-carboxylic
acid benzyl ester
[0831] ##STR468##
[0832] The
3-(1-tert-butoxycarbonylamino-2-cyano-ethyl)-pyrrolidine-1-carboxylic
acid benzyl ester isomeric mixture was first purified over silica
gel column with 25 to 75% ethyl acetate in hexanes over 50 minutes
to give diastereomers A and B. Diastereomer A was subjected to
chiral HPLC (Chiralpak AD, 10% ethanol in methanol) to give
enantiomers A1 (8.4 minutes) and A2 (12.2 minutes).
[0833] To a solution of
3-(1-tert-butoxycarbonylamino-2-cyano-ethyl)-pyrrolidine-1-carboxylic
acid benzyl ester (0.53 g, 1.41 mmol) in methanol (25 mL) under
nitrogen atmosphere were added ammonium formate (0.27 g, 4.23 mmol)
and 10% Pd/C (0.25 g). The nitrogen source was removed and the
reaction flask was capped. After 2 days, the reaction mixture was
filtered through celite and the filtrate was concentrated in vacuo
to give 0.34 g of title compound as a mixture of isomers (100%). MS
(APCI+): m/z 240 (M+H).sup.+.
EXAMPLE 11
Preparation of Pyrrolidin-3-yl-acetonitrile
[0834] ##STR469##
A. 3-(Toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid
benzyl ester
[0835] ##STR470##
[0836] To a solution of 3-hydroxymethyl-pyrrolidine-1-carboxylic
acid benzyl ester (1.80 g, 7.65 mmol) in dichloromethane (10 mL)
were added triethylamine (1.60 mL, 11.48 mmol) and
p-toluenesulfonyl chloride (1.75 g, 9.18 mmol). After 3 hours, the
reaction mixture washed with saturated sodium bicarbonate, water
and brine. The organic layer was dried over MgSO.sub.4, filtered
and filtrate concentrated. Purification via flash column
chromatography (ethyl acetate/hexanes gradient) afforded 2.63 g of
the title compound (88% yield). MS (APCI+): m/z 390
(M+H).sup.+.
B. 3-Cyanomethyl-pyrrolidine-1-carboxylic acid benzyl ester
[0837] ##STR471##
[0838] To a solution of
3-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid
benzyl ester (1.52 g, 3.90 mmol) in DMSO (3 mL) was added sodium
cyanide (0.25 g, 5.07 mmol). The reaction mixture was heated to
70.degree. C. After 4 hours, the reaction mixture was poured into
saturated sodium bicarbonate and extracted with ethyl acetate. The
organic layer was dried over MgSO.sub.4, filtered and the filtrate
was concentrated at reduced pressure. Purification via flash column
chromatography (ethyl acetate/hexanes gradient) afforded 0.81 g of
the title compound (85%). MS (APCI+): m/z 245 (M+H).sup.+.
C. Pyrrolidin-3-yl-acetonitrile
[0839] ##STR472##
[0840] To a solution of 3-cyanomethyl-pyrrolidine-1-carboxylic acid
benzyl ester (0.80 g, 3.27 mmol) in methanol (50 mL) were added
triethylamine (0.5 mL) and 10% Pd/C (0.2 g). The reaction vessel
was pressurized to 50 psi for 24 hours, filtered through celite,
and the filtrate was concentrated at reduced pressure to give 0.36
g of the title compound (100% yield). MS (APCI+): m/z 111
(M+H).sup.+.
EXAMPLE 12
Preparation of
3-Amino-3-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-t-
etrahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-propionitrile
Hydrochloride salt
[0841] ##STR473##
A. Pyrrolidine-3-carboxylic acid ethyl ester
[0842] ##STR474##
[0843] A solution of 1-benzyl-pyrrolidine-3-carboxylic acid ethyl
ester (10.00 g, 42.9 mmol) in ethanol (200 mL) was hydrogenated in
the presence of 10% Pd/C (2.0 g) at 60 psi for 6 hours. The
resulting suspension was filtered through celite, washed with
CH.sub.2Cl.sub.2, and concentrated under reduced pressure to leave
the crude title compound (7.12 g, 100% yield). .sup.1H NMR
.quadrature.(CDCl.sub.3) 4.16 (q, 2H), 3.02-3.17 (m, 3H), 2.82-2.94
(m, 2H), 1.91-2.07 (m, 2H), 1.26 (t, 3H). LCMS (APCI.sup.+) 144
(100%, MH.sup.+).
B. Pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl
ester
[0844] ##STR475##
[0845] To a solution of crude pyrrolidine-3-carboxylic acid ethyl
ester (7.12 g) in CH.sub.2Cl.sub.2 (50 mL) at 0.degree. C. was
added a solution of di-tert-butyl dicarbonate (10.30 g, 47.2 mmol)
in CH.sub.2Cl.sub.2 (50 mL) over 10 minutes. After warming to room
temperature over 18 hours, the reaction mixture washed with water,
then brine, dried (Na.sub.2SO.sub.4) and concentrated under reduced
pressure to leave the title compound which was used without further
purification (10.4 g, 100% yield). .sup.1H NMR
.quadrature.(CDCl.sub.3) 4.14 (q, 2H), 3.27-3.69 (m, 4H), 3.02 (m,
1H), 2.07-2.16 (m, 2H), 1.46 (s, 9H), 1.27 (t, 3H).
C. 3-Hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl
ester
[0846] ##STR476##
[0847] To a solution of pyrrolidine-1,3-dicarboxylic acid
1-tert-butyl ester 3-ethyl ester (10.4 g, 42.9 mmol) in
tetrahydrofuran (50 mL) and methanol (50 mL) at 0.degree. C. was
added sodium borohydride (NaBH) (3.25 g, 86 mmol) in portions over
30 minutes. After 18 hours, more NaBH (3.25 g, 86 mmol) was added.
After a further 24 hours, the reaction mixture was diluted with
ethyl acetate, quenched with saturated aqueous Na.sub.2CO.sub.3 and
stirred for 15 minutes. The layers were separated, the aqueous
layer extracted with ethyl acetate, and then the combined organic
layers washed twice with water, once with brine, dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure. The
crude product was purified by column chromatography
(CH.sub.2Cl.sub.2 to CH.sub.2Cl.sub.2:MeOH 95:5 to 9:1) to give the
title compound (8.09 g, 94% yield). .sup.1H NMR
.quadrature.(CDCl.sub.3) 3.25-3.69 (m, 5H), 3.11 (m, 1H), 2.40 (m,
1H), 1.97 (m, 1H), 1.67 (m, 1H), 1.46 (s, 9H).
D. 3-Formyl-pyrrolidine-1-carboxylic acid tert-butyl ester
[0848] ##STR477##
[0849] To a solution of oxalyl chloride (3.86 mL, 44.2 mmol) in
CH.sub.2Cl.sub.2 (80 mL) at -78.degree. C. under N.sub.2 was added
a solution of dimethyl sulfoxide (6.28 mL, 88.5 mmol) in
CH.sub.2Cl.sub.2 (20 mL). After 10 minutes, a solution of
3-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester
(8.09 g, 40.2 mmol) in CH.sub.2Cl.sub.2 (30 mL) was added over 15
minutes. After a further 30 minutes, triethylamine (28.0 mL, 201
mmol) was added, and the reaction mixture was stirred for 1 hour at
-78.degree. C. then 1 hour at room temperature. The reaction
mixture washed twice with water then with brine, dried
(Na.sub.2SO.sub.4) and concentrated under reduced pressure. The
crude product was purified by column chromatography (hexanes:ethyl
acetate 9:1 to 1:1) to give the title compound (6.98 g, 87%).
.sup.1H .quadrature.(CDCl.sub.3) 9.69 (d, J=1.7 Hz, 1H), 3.26-3.80
(m, 4H), 3.03 (m, 1H), 2.02-2.29 (m, 2H), 1.46 (s, 9H).
E.
3-(Benzenesulfonyl-tert-butoxycarbonylamino-methyl)-pyrrolidine-1-carbo-
xylic acid tert-butyl ester
[0850] ##STR478##
[0851] To a suspension of tert-butyl carbamate (589 mg, 5.03 mmol)
and sodium benzenesulfinate (1.24 g, 7.55 mmol) in water (50 mL)
was added a solution of 3-formyl-pyrrolidine-1-carboxylic acid
tert-butyl ester (1.00 g, 5.03 mmol) in methanol (5 mL), followed
by formic acid (0.19 mL, 5.03 mmol). The reaction mixture was
heated to 60.degree. C. for 2 hours, then stood at room temperature
for 7 days. The resulting white solid was filtered off, washed with
water and dried thoroughly under reduced pressure to give the title
compound (868 mg, 39% yield). .sup.1H NMR .quadrature.(CDCl.sub.3)
7.91 (d, 2H), 7.50-7.68 (m, 3H), 4.82-5.18 (m, 2H), 3.71 (m, 1H),
3.54 (m, 1H), 3.31 (m, 1H), 2.90-3.19 (m, 2H), 2.35 (m, 0.5H), 2.18
(m, 0.5H), 1.76-1.99 (m, 1H), 1.47 (s, 9H), 1.21 (s, 4.5H), 1.18
(s, 4.5H.
F.
3-(1-tert-Butoxycarbonylamino-2-cyano-2,2-dimethyl-ethyl)-pyrrolidine-1-
-carboxylic acid tert-butyl ester
[0852] ##STR479##
[0853] To solution isobutyronitrile (4.07 mL, 45 mmol) in dry THF
(100 mL) at -78.degree. C. under an atmosphere of nitrogen was
added lithium diisopropylamide (30.3 mL of a 1.5 M solution in
cyclohexane, 45 mmol). After 1 hour, this solution was transferred
by cannula to a stirred suspension of
3-(benzenesulfonyl-tert-butoxycarbonylamino-methyl)-pyrrolidine-1-carboxy-
lic acid tert-butyl ester (2.00 g, 4.55 mmol) in dry THF (100 mL)
at -78.degree. C. After 7 hours, the reaction was slowly warmed to
room temperature overnight. The reaction was then quenched with
saturated aqueous ammonium chloride (NH.sub.4Cl) and extracted
twice with CH.sub.2Cl.sub.2. The organic phase washed with
saturated aqueous NaHCO.sub.3, then dried (Na.sub.2SO.sub.4) and
concentrated under reduced pressure. The crude product was purified
by column chromatography, firstly with hexanes: EtOAc 3:1 to 2:1,
and then with CH.sub.2Cl.sub.2: MeOH 99.5:0.5 to 99:1) to give the
title compound (1.52 g, 91% yield). .sup.1H NMR
.quadrature.(CDCl.sub.3) 4.64-4.79 (m, 1H), 3.42-3.85 (m, 3H),
2.93-3.29 (m, 2H), 2.54 (m, 1H), 1.96-2.14 (m, 1H), 1.74-1.80 (m,
1H), 1.35-1.47 (m, 24H). LCMS (APCI.sup.-) 366 (100%,
(M-H).sup.-).
G. 3-Amino-2,2-dimethyl-3-pyrrolidin-3-yl-propionitrile
dihydrochloride salt
[0854] ##STR480##
[0855] To a solution of
3-(1-tert-butoxycarbonylamino-2-cyano-2,2-dimethyl-ethyl)-pyrrolidine-1-c-
arboxylic acid tert-butyl ester (1.52 g, 4.3 mmol) in
CH.sub.2Cl.sub.2 (100 mL) at 0.degree. C. was added HCl (21.5 mL of
a 4 M solution in dioxane, 86 mmol). After 10 minutes, the reaction
mixture was warmed to room temperature and stirred for 18 hours
before it was concentrated under reduced pressure. The oily residue
was taken up in water, extracted twice with CH.sub.2Cl.sub.2, and
the aqueous phase concentrated under reduced pressure to give the
title compound (704 mg, 73%). .sup.1H NMR .quadrature.(D.sub.2O)
3.68-3.82 (m, 2H), 3.52-3.63 (m, 1H), 3.17-3.45 (m, 2H), 2.86-3.12
(m, 1H), 2.46 (m, 1H), 1.89-2.10 (m, 1H), 1.60 (s, 1.5H), 1.59 (s,
1.5H), 1.57 (s, 1.5H), 1.56 (s, 1.511). LCMS (APCI.sup.+) 168
(100%, MH.sup.+).
EXAMPLE 13
Preparation of
(.+-.)-N-[1-azetidin-3-yl)-2-cyanoethyl]-2,2,2-trifluoroacetamide
hydrochloride
[0856] ##STR481##
A. Cis/trans-3-(1-Benzhydrylazetidin-3-yl)-acrylonitrile
[0857] ##STR482##
[0858] A solution of 1-benzhydrylazetidine-3-carbaldehyde (1.55 g,
6.17 mmol), diethyl(cyanomethyl)phosphonate (1.30 mL, 8.02 mmol),
and cesium carbonate (2.61 g, 8.02 mmol) in tetrahydrofuran (30 mL)
was heated at 50.degree. C. for 2 hours. The solution was cooled to
room temperature and diluted with ethyl acetate (100 mL). The
solution was then washed with saturated aqueous ammonium chloride
(20 mL). The organic layer was then dried (magnesium sulfate),
filtered, and concentrated under reduced pressure. The resulting
residue was purified via medium pressure liquid chromatography
eluting with a gradient of hexanes:ethyl acetate (90:10 to 75:25)
to deliver 913 mg (54%) of the title compound as a 1:1 mixture of
cis/trans-isomers. The isomers were collected separately but later
combined. cis-isomer: MS (APCI) (M+1)/Z 275.0; m.p.=117-120.degree.
C. trans-isomer: MS (APCI) (M+1/Z) 275.0; m.p.=108-110.degree.
C.
B. (.+-.)-3-Amino-3-(1-benzhydrylazetidin-3-yl)-propionitrile
[0859] ##STR483##
[0860] A saturated solution of ammonia in methanol (30 mL) was
added to a 1:1 mixture of
cis/trans-3-(1-benzhydrylazetidin-3-yl)-acrylonitrile (863 mg, 3.15
mmol). The resulting suspension was then heated in a sealed tube at
100.degree. C. for 19 hours. After cooling to room temperature, the
solution was concentrated under reduced pressure to deliver 912 mg
(99.5%) of the title compound as an oil. MS (APCI) (M+1)/Z
292.1.
C.
(.+-.)--N-[1-(1-benzhydryl-azetidin-3-yl)-2-cyanoethyl]-2,2,2-trifluoro-
acetamide
[0861] ##STR484##
[0862] A solution of
3-amino-3-(1-benzhydrylazetidin-3-yl)-propionitrile (905 mg, 3.11
mmol) and triethylamine (1.30 mL, 9.32 mmol) in dichloromethane (30
mL) at 0.degree. C. was treated with trifluoroacetic anhydride
(0.659 mL, 4.67 mmol). The solution was then stirred at room
temperature for 45 minutes. The solution was then cooled to
0.degree. C., and water (5 mL) was added. The mixture was then
further diluted with dichloromethane (50 mL) and water (15 mL). The
layers were separated, and the organic layer washed with water
(2.times.20 mL). The organic layer was then dried (magnesium
sulfate), filtered, and concentrated under reduced pressure. The
resulting residue was purified via medium pressure liquid
chromatography eluting with a gradient of hexanes:ethyl acetate
(75:25 to 55:45) to deliver 952 mg (79%) of the title compound. MS
(APCI) (M+1)/Z 388.0.
D.
(.+-.)-N-[1-azetidin-3-yl)-2-cyanoethyl]-2,2,2-trifluoroacetamide
hydrochloride
[0863] ##STR485##
[0864] A solution of
N-[1-(1-benzhydrylazetidin-3-yl)-2-cyanoethyl]-2,2,2-trifluoroacetamide
(491 mg, 1.27 mmol) in dichloroethane (15 mL) was cooled to
0.degree. C., whereupon, 1-chloroethyl chloroformate (0.410 mL,
3.80 mmol) was added. The resulting solution was heated at reflux
for 2 hours. The solution was then concentrated under reduced
pressure to deliver an oil. Methanol (15 mL) was added to the oil,
and the resulting solution was heated at reflux for 2 hours. The
solvent was removed under reduced pressure to deliver a thick
yellow oil. The oil was triturated with hexanes several times, and
the supernatant was discarded. The title compound was delivered as
a yellow residue, 391 mg. MS (APCI) (M+1)/Z 222.0.
EXAMPLE 14
Preparation of (2-Cyano-1-pyrrolidin-3-yl-ethyl)-methyl-carbamic
acid tert-butyl ester
A.
3-(1-tert-Butoxycarbonylamino-2-cyano-ethyl)-pyrrolidine-1-carboxylic
acid benzyl ester
[0865] ##STR486##
[0866] To a solution of 3-(2-cyano-vinyl)-pyrrolidine-1-carboxylic
acid benzyl ester (4.40 g, 17.2 mmol) in absolute ethanol (50 mL)
was added methyl amine (approximately 3 mL) and the solution was
heated in a sealed reactor at 80.degree. C. for 14 hours. The
solution was concentrated in vacuo. The resulting amine was
dissolved in THF (100 mL), Boc anhydride (5.62 g, 25.7 mmol) was
added, and the solution was stirred at room temperature for 17
hours. The solution was conc. in vacuo. The residue was taken up in
ethyl acetate (100 mL), washed with satd. aq. NH.sub.4Cl (100 mL)
and brine (100 mL), dried with MgSO.sub.4 and concentrated in
vacuo. The crude product was purified on a 120 g silica gel column
eluted with 20 to 60% ethyl acetate in hexanes over 60 minutes at
50 mL/min to give 6.08 g of the title compound in multiple
fractions (combined yield: 91%). MS (APCI+): m/z 288 (M+H-Boc).
Diastereomer A (top spot) yield was 2.59 g (39%) and diastereomer B
(bottom spot) yield was 2.82 g (42%). ##STR487## Diastereomer B
(2.1 g) was separated by chiral HPLC using a ChiralPak AD column
eluted with a methanol/ethanol gradient to give 0.87 g of isomer B1
(41%) and 0.53 g of isomer B2 (25%).
B. (2-Cyano-1-pyrrolidin-3-yl-ethyl)-methyl-carbamic acid
tert-butyl ester
[0867] ##STR488##
[0868] A solution of
3-(1-tert-butoxycarbonylamino-2-cyano-ethyl)-pyrrolidine-1-carboxylic
acid benzyl ester (diastereomer B, 0.690 g, 1.78 mmol) in THF (50
mL) was hydrogenated with 10% Pd/C. The catalyst was removed by
filtration and the filtrate was concentrated in vacuo to give 0.436
g of title compound (yield: 97%). MS (APCI+): m/z 254 (M+H).
EXAMPLE 15
Alternative Preparation of
3-(1-tert-Butoxycarbonylamino-2-cyano-ethyl)-pyrrolidine-1-carboxylic
acid benzyl ester
[0869] ##STR489##
[0870] To a solution of
3-(1-tert-butoxycarbonylamino-2-cyano-ethyl)-pyrrolidine-1-carboxylic
acid benzyl ester (isomer B2) (586 mg, 1.57 mmol) in anhydrous DMF
(12 mL) was added NaH (60 wt %, 188 mg, 4.71 mmol) and the solution
was stirred at room temperature for 1 hour. Methyl iodide (1.78 g,
12.5 mmol) was then added to the mixture and it was stirred at room
temperature for 1 hour. The solution was poured into satd. aq.
NH4Cl (80 mL) and extracted with diethyl ether (120 mL). The
organics were washed with brine (50 mL), dried with MgSO.sub.4 and
concentrated in vacuo. The crude was run on a 10 g silical gel
column eluted with 20 to 70% ethyl acetate in hexanes over 1 hour
to give 0.44 g of the title compound (yield: 72%). MS (APCI+): m/z
288 (M+H-Boc).
B. Coupling of Sidechain Precursors to Aminoquinazolinedione
Cores
[0871] Coupling of the sidechain precursor to the quinazolinedione
core precursor to provide the compounds of the present invention
occurs as described in WO/02 102793, priority date Jun. 19, 2001
and WO/01 53273, priority date Oct. 18, 2000, and references cited
therein, or as indicated below.
EXAMPLE 14
Preparation of
3-Amino-3-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4--
tetrahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-propionitrile
[0872] ##STR490##
[0873] To a solution of 3-amino-3-pyrrolidin-3-yl-propionitrile
(0.350 g, 2.51 mmol)) in DMSO (4 mL) was added
3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione
(0.475 g, 1.68 mmol) followed by 1,1,3,3-tetramethylguanidine
(0.420 mL, 3.35 mmol). The reaction mixture was heated to
90.degree. C. and stirred overnight. The reaction mixture was
poured into water and extracted with ethyl acetate. The organic
layer was dried over magnesium sulfate, filtered and concentrated.
The crude residue was purified by flash column chromatography (0 to
4% methanol in dichloromethane) to afford 410 mg of the crude title
compound. The product was dissolved in dichloromethane and HCl gas
was bubbled in for 5 minutes. The mixture was concentrated, and the
remaining solid was precipitated from hot ethanol. The mixture was
filtered to give 310 mg (50% yield) of the title compound as the
HCl salt. MS (APCI+): m/z 403 (M+H).sup.+.
EXAMPLE 15
Preparation of
3-Amino-3-[1-(3-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahy-
dro-quinazolin-7-yl)-pyrrolidin-3-yl]-propionitrile
[0874] ##STR491##
[0875] To a solution of 3-amino-3-pyrrolidin-3-yl-propionitrile
(0.200 g, 1.44 mmol)) in DMSO (3 mL) was added
1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione (0.242
g, 0.958 mmol) followed by 1,1,3,3-tetramethyl guanidine (0.180 mL,
1.44 mmol). The reaction mixture was heated to 90.degree. C. and
stirred overnight. The reaction mixture was poured into water and
extracted with ethyl acetate. The organic layer was dried over
magnesium sulfate, filtered and concentrated. The crude residue was
purified by flash column chromatography (0 to 5% methanol in
dichloromethane) to afford 87 mg of the crude product. The product
was dissolved in dichloromethane and a saturated solution of HCl in
dichloromethane (3 mL) was added. After stirring for 15 minutes,
the mixture was concentrated and the remaining solid was
precipitated from hot ethanol. The mixture was filtered to give 39
mg (11% yield) of the title compound as the HCl salt. MS (APCI+):
m/z 370 (M+H).sup.+.
EXAMPLE 16
Preparation of
3-Amino-3-[1-(3-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahy-
dro-quinazolin-7-yl)-pyrrolidin-3-yl]-propionitrile
[0876] ##STR492##
[0877] To a solution of 3-amino-3-pyrrolidin-3-yl-propionitrile
(0.307 g, 2.21 mmol)) in DMSO (4 mL) was added
3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
(0.393 g, 1.47 mmol) followed by 1,1,3,3-tetramethylguanidine
(0.369 mL, 2.94 mmol). The reaction mixture was heated to
90.degree. C. and stirred overnight. The reaction mixture was
poured into water and extracted with ethyl acetate. The organic
layer was dried over magnesium sulfate, filtered and concentrated.
The crude residue was purified by flash column chromatography (0 to
4% methanol in dichloromethane) to afford 210 mg (37%) of the title
compound. MS (APCI+): m/z 387 (M+H).sup.+.
EXAMPLE 17
Preparation of
3-[2-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-octahydro-cyclopenta[c]pyrrol-4-ylamino]-propionitrile
A.
[2-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-octahydro-cyclopenta[c]pyrrol-4-yl]-carbamic
acid tert-butyl ester
[0878] ##STR493##
[0879] To a solution of
3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione
[WO 01/53273] (0.500 g, 1.77 mmol) in dimethylsulfoxide (4 mL) was
added (octahydro-cyclopenta[c]pyrrol-4-yl)-carbamic acid tert-butyl
ester [WO 96/39407] (1.2 g, 5.1 mmol), and the reaction mixture was
heated at 110.degree. C. After 5 hours, the mixture was cooled to
room temperature and water was added. The resulting solid was
filtered and purified on a 40M Biotage flash column (4:1 ethyl
acetate/hexanes) to afford the title compound (0.470 g, 54%) as a
white solid. MS: m/z 490.0 (M+H).sup.+.
B.
3-Amino-7-(4-amino-hexahydro-cyclopenta[c]pyrrol-2-yl)-1-cyclopropyl-6--
fluoro-8-methoxy-1H-quinazoline-2,4-dione
[0880] ##STR494##
[0881] To a solution of
[2-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydro-
-quinazolin-7-yl)-octahydro-cyclopenta[c]pyrrol-4-yl]-carbamic acid
tert-butyl ester (0.470 g, 0.96 mmol) in ethyl acetate (5 mL) was
added 5 mL of saturated hydrochloric acid in ethanol, and the
reaction mixture was allowed to stir for 5 hours. The solvent was
removed in vacuo, and the product was recrystallized from 4 mL of
2:1 ethanol/isopropyl alcohol to afford the title compound (0.258
g, 69%); mp 250-252.degree. C.
C. Preparation of
3-[2-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-octahydro-cyclopenta[c]pyrrol-4-ylamino]-propionitrile
[0882] ##STR495##
[0883] To a cooled (0.degree. C.) solution of
3-amino-7-(4-amino-hexahydro-cyclopenta[c]pyrrol-2-yl)-1-cyclopropyl-6-fl-
uoro-8-methoxy-1H-quinazoline-2,4-dione (0.125 g, 0.321 mmol) and
triethylamine (89.5 .mu.L, 0.642 mmol) in methanol (1 mL) was added
acrylonitrile (23.2 .mu.L, 0.353 mmol). The reaction mixture was
allowed to warm to room temperature and stirred for 18 hours. The
volatiles were removed in vacuo, and the resulting residue was
purified on a 12 g Isco flash column (0:100 to 5:95
methanol/dichloromethane) to afford the title compound (88 mg,
62%). MS (APCI+): m/z 443.3 (M+H).sup.+.
EXAMPLE 18
Preparation of
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-4-methyl-pyrrolidin-3-ylmethyl]-amino}-propionitrile
[0884] ##STR496##
[0885] To a cooled (0.degree. C.) solution of
3-amino-7-(trans-3-aminomethyl-4-methylpyrrolidin-1-yl)-1-cyclopropyl-6-f-
luoro-8-methyl-1H-quinazoline-2,4-dione hydrochloride [WO 01/53273]
(0.022 g, 0.061 mmol) and triethylamine (17.0 .mu.L, 0.122 mmol) in
methanol (0.5 mL) was added acrylonitrile (4.4 .mu.L, 0.067 mmol).
The reaction mixture was allowed to warm to room temperature and
stirred for 18 hours. The volatiles were removed in vacuo, and the
resulting residue was purified via flash column (0:100 to 5:95
methanol/dichloromethane) to afford the title compound (10.5 mg,
42%) as a white solid. MS: m/z 415.0 (M+H).sup.+.
EXAMPLE 19
Preparation of
3-({[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahy-
dro-quinazolin-7-yl)-pyrrolidin-3-yl]-oxazol-2-yl-methyl}-amino)-propionit-
rile
A.
3-Amino-7-[3-(amino-oxazol-2-yl-methyl)-pyrrolidin-1-yl]-1-cyclopropyl--
6-fluoro-8-methyl-1H-quinazoline-2,4-dione
[0886] ##STR497##
[0887] To a mixture of
3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
[WO 01/53273] (0.36 g, 2.2 mmol) and
C-Oxazol-2-yl-C-pyrrolidin-3-yl-methylamine (0.41 g, 1.5 mmol) in
dimethylsulfoxide (1.5 mL) was added 1,1,3,3-tetramethylguanidine
(0.70 mL, 0.65 mmol). The reaction mixture was heated at 85.degree.
C. for 48 hours, cooled to the room temperature, treated with brine
(20 mL), and extracted with ethyl acetate (2.times.20 mL). The
combined organic extracts were washed with brine, dried over sodium
sulfate, filtered, and concentrated in vacuo. The resulting residue
was purified by flash chromatography (19:1
dichloromethane/methanol) to afford the title compound, which was
used in the next step without further purification.
B.
{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-pyrrolidin-3-yl]-oxazol-2-yl-methyl}-carbamic
acid tert-butyl ester
[0888] ##STR498##
[0889] To the solution of
3-Amino-7-[3-(amino-oxazol-2-yl-methyl)-pyrrolidin-1-yl]-1-cyclopropyl-6--
fluoro-8-methyl-1H-quinazoline-2,4-dione (0.2 g) in dichloromethane
(15 mL) was added triethylamine (0.16 mL) and di-tert-butyl
dicarbonate (0.14 g), and the mixture was stirred at room
temperature for 18 hours. The solvent was removed in vacuo, and the
residue was purified by flash chromatography (9:1 ethyl
acetate/methanol) to afford the title compound (0.24 g, 31%).
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.74-7.55 (m, 2H), 7.11
(d, 1H), 5.42-4.98 (m, 4H), 3.61-3.25 (m, 5H), 2.94-2.77 (m, 1H),
2.39 (d, 3H), 2.21-1.79 (m, 2H), 1.41 (s, 9H), 1.21-0.90 (m, 2H),
0.69-0.52 (m, 2H).
C.
3-Amino-7-[3-(amino-oxazol-2-yl-methyl)-pyrrolidin-1-yl-1-cyclopropyl-6-
-fluoro-8-methyl-1H-quinazoline-2,4-dione
[0890] ##STR499##
[0891] To a solution of
{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-
-quinazolin-7-yl)-pyrrolidin-3-yl]-oxazol-2-yl-methyl}-carbamic
acid tert-butyl ester (0.24 g, 0.47 mmol) in dichloromethane (5 mL)
was added 15 mL of saturated hydrogen chloride gas in diethyl
ether, and the reaction mixture was stirred for 2 hours. The
solvent was removed in vacuo to afford a white solid which was
triturated with diethyl ether to afford the title compound (0.17 g,
79%). MS: m/z 414.9 (M+H).sup.+.
D.
3-({[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-pyrrolidin-3-yl]-oxazol-2-yl-methyl}-amino)-propion-
itrile
[0892] ##STR500##
[0893] To a cooled (0.degree. C.) solution of
3-Amino-7-[3-(amino-oxazol-2-yl-methyl)-pyrrolidin-1-yl]-1-cyclopropyl-6--
fluoro-8-methyl-1H-quinazoline-2,4-dione (0.083 g, 0.20 mmol) and
triethylamine (55.8 .mu.L, 0.400 mmol) in methanol (1 mL) was added
acrylonitrile (43.5 .mu.L, 0.661 mmol). The reaction mixture was
allowed to warm to room temperature and stirred for 72 hours. The
volatiles were removed in vacuo, and the resulting residue was
purified on a 12 g Isco flash column (0:100 to 5:95
methanol/dichloromethane) to afford the title compound (19.1 mg,
20%) as a 60:40 mixture of diastereomers as a yellow solid. MS: m/z
468.1 (M+H).sup.+.
EXAMPLE 20
Preparation of
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-4-fluoro-pyrrolidin-3-ylmethyl]-amino}-propionitrile
A.
[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydr-
o-quinazolin-7-yl)-4-fluoro-pyrrolidin-3-ylmethyl]-carbamic acid
tert-butyl ester
[0894] ##STR501##
[0895] A mixture of
3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
[WO 01/53273] (0.37 g, 1.38 mmol),
trans-(4-fluoropyrrolidine-3-ylmethyl)carbamic acid tert-butyl
ester [WO 01/53273] (0.60 g, 2.7 mmol), and triethylamine (0.77 mL,
5.5 mmol) in dimethyl sulfoxide (4 mL) was heated in a sealed tube
at 120.degree. C. for 2 days. The mixture was cooled, diluted with
water, and extracted with ethyl acetate. The combined organic
extracts were dried over sodium sulfate, filtered, and concentrated
in vacuo. The residue was purified by preparative thin layer
chromatography (8:92 methanol/dichloromethane) to afford the title
compound (0.09 g, 14%) as a thick oil. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.00 (br s, 1H), 7.58 (d, 1H), 5.18 (br s, 2H),
5.07 (d, 1H), 3.96-3.83 (m, 1H), 3.58-3.39 (m, 2H), 3.35-3.09 (m,
2H), 3.04-2.82 (m, 1H), 2.80-2.40 (m, 5H), 1.51 (s, 9H), 1.20 (m,
2H), 0.68 (m, 2H).
B.
3-Amino-7-(3-aminomethyl-4-fluoro-pyrrolidin-1-yl)-1-cyclopropyl-6-fluo-
ro-8-methyl-1H-quinazoline-2,4-dione
[0896] ##STR502##
[0897] Hydrogen chloride gas was bubbled into a cooled (0.degree.
C.) solution of
[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro--
quinazolin-7-yl)-4-fluoro-pyrrolidin-3-ylmethyl)-carbamic acid
tert-butyl ester (0.090 g, 0.19 mmol) in anhydrous ethanol (4 mL)
for 10 minutes. The suspension was slowly warmed to room
temperature and stirred for 16 hours. The solvent was evaporated in
vacuo, washed with diethyl ether, and dried to provide the title
compound (0.76 g); mp 170-172.degree. C.
C.
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrah-
ydro-quinazolin-7-yl)-4-fluoro-pyrrolidin-3-ylmethyl]-amino}-propionitrile
[0898] ##STR503##
[0899] To a cooled (0.degree. C.) solution of
3-amino-7-(3-aminomethyl-4-fluoro-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-
-8-methyl-1H-quinazoline-2,4-dione (0.037 g, 0.101 mmol) and
triethylamine (28.2 .mu.L, 0.202 mmol) in methanol (1 mL) was added
acrylonitrile (7.3 .mu.L, 0.11 mmol). The reaction mixture was
allowed to warm to room temperature and stirred for 65 hours. The
volatiles were removed in vacuo, and the resulting residue was
purified on a 12 g Isco flash column (0:100 to 5:95
methanol/dichloromethane) to afford the title compound (23.0 mg,
54%) as a yellow solid. MS: m/z 419.2 (M+H).sup.+.
EXAMPLE 21
Preparation of
3-Amino-3-[1-(1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydr-
o-quinazolin-7-yl)-pyrrolidin-3-yl]-propionitrile
A.
{2-Cyano-1-[1-(1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrah-
ydro-quinazolin-7-yl)-pyrrolidin-3-yl]-ethyl}-carbamic acid
tert-butyl ester
[0900] ##STR504##
[0901] To a solution of (2-cyano-1-pyrrolidin-3-yl-ethyl)-carbamic
acid tert-butyl ester (0.340 g, 1.4 mmol)) in DMSO (4 mL) was added
1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione (0.240
g, 0.96 mmol) followed by 1,1,3,3-tetramethylguanidine (0.180 mL,
1.4 mmol). The reaction mixture was heated to 90.degree. C. and
stirred overnight. The reaction mixture was poured into water and
extracted with ethyl acetate. The organic layer was dried over
magnesium sulfate, filtered and concentrated. The crude residue was
purified by flash column chromatography (0 to 70% ethyl acetate in
hexanes) to afford 130 mg (29%) of the title compound. MS (APCI+):
m/e 472 (M+H).sup.+.
B.
3-Amino-3-[1-(1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahy-
dro-quinazolin-7-yl)-pyrrolidin-3-yl]-propionitrile
[0902] ##STR505##
[0903] To a solution of
{2-Cyano-1-[1-(1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-pyrrolidin-3-yl]-ethyl}-carbamic acid
tert-butyl ester (0.13 g, 0.28 mmol) in dichloromethane (10 mL) was
bubbled in HCl gas for 2 minutes. The reaction mixture stirred for
3 hours and was concentrated. 1N NaOH solution was added and the
mixture was concentrated. The crude residue was purified by flash
chromatography (0-10% methanol in dichloromethane) to afford 50 mg
(50%) of the crude product. The mixture was dissolved in ethanol (5
mL) and 10% HCl in ethanol was added. The mixture was concentrated
to give the title compound as the HCl salt. MS (APCI+): m/e 372
(M+H)+.
EXAMPLE 22
Preparation of
3-{1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetra-
hydro-quinazolin-7-yl)-pyrrolidin-3-yl]-ethylamino}-propionitrile
[0904] ##STR506##
[0905] To a solution of
3-Amino-7-[3-(1-amino-ethyl)-pyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-me-
thoxy-1H-quinazoline-2,4-dione (0.31 g, 0.81 mmol) in methanol (4
mL) was added triethylamine (0.23 mL, 1.6 mmol) followed by
acrylonitrile (0.064 mL, 0.98 mmol). The reaction stirred at room
temperature overnight. An additional 0.042 mL of acrylonitrile was
added and the mixture stirred overnight again. The reaction mixture
was concentrated and the crude residue purified by flash column
chromatography (0 to 5% methanol in dichloromethane) to afford the
title compound as the free amine, which was diluted with
dichloromethane. HCl gas was bubbled in for 30 sec. The mixture was
concentrated to afford 165 mg (47%) of the title compound as the
HCl salt. MS (APCI+): m/e 431 (M+H).sup.+.
EXAMPLE 23
Preparation of
[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydro--
quinazolin-7-yl)-pyrrolidin-3-yl]-acetonitrile
[0906] ##STR507##
[0907] To a solution of
3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
(0.35 g, 1.31 mmol) in DMSO (3 mL) were added
pyrrolidin-3-yl-acetonitrile (0.21 g, 1.97 mmol) and
1,1,3,3-tetramethylguanidine (0.30 g, 2.62 mmol). The reaction
mixture was heated to 90.degree. C. After 20 hours, the reaction
mixture was poured into saturated sodium bicarbonate solution and
extracted with ethyl acetate. The organic layer was dried over
MgSO.sub.4, filtered, and filtrate concentrated. The crude residue
was purified by flash column chromatography (50% ethyl acetate in
hexanes to 100% ethyl acetate) to afford 110 mg of the title
compound (23% yield). MS (APCI+): m/z 358 (M+H).sup.+.
EXAMPLE 24
Preparation of
3-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydr-
o-quinazolin-7-yl)-pyrrolidin-3-yl]-3-methylamino-propionitrile
A.
{1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrah-
ydro-quinazolin-7-yl)-pyrrolidin-3-yl]-2-cyano-ethyl}-carbamic acid
tert-butyl ester
[0908] ##STR508##
[0909] To a solution of
3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
(0.31 g, 1.16 mmol) in DMSO (2 mL) were added
(2-cyano-1-pyrrolidin-3-yl-ethyl)-carbamic acid tert-butyl ester
(0.33 g, 1.39 mmol) and tetramethylguanidine (0.27 g, 2.32 mmol).
The reaction mixture was heated to 90.degree. C. After 20 hours,
the reaction mixture was poured into saturated sodium bicarbonate
solution and extracted with ethyl acetate. The organic layer was
dried over MgSO.sub.4, filtered, and filtrate concentrated. The
crude residue was purified by flash column chromatography (50%
ethyl acetate in hexanes to 100% ethyl acetate over 50 minutes) to
afford 133 mg of the title compound (24%). MS (APCI+): m/z 487
(M+H).sup.+.
B.
3-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahy-
dro-quinazolin-7-yl)-pyrrolidin-3-yl]-3-methylamino-propionitrile
[0910] ##STR509##
[0911] To a solution of
{1-[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahyd-
ro-quinazolin-7-yl)-pyrrolidin-3-yl]-2-cyano-ethyl}-carbamic acid
tert-butyl ester (0.13 g, 0.27 mmol) in dichloromethane (5 mL) was
added HCl (2M in ether, 2 mL, 4 mmol). After 5 hours, the
precipitate formed was filtered, washed with hexanes and dried
under vacuo to give 0.11 g of title compound as the HCl salt
(97%).
EXAMPLE 25
Preparation of
3-Amino-3-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-t-
etrahydro-quinazolin-7-yl)-pyrrolidin-3-yl]-2,2-dimethyl-propionitrile
[0912] ##STR510##
[0913] A solution of
3-amino-2,2-dimethyl-3-pyrrolidin-3-yl-propionitrile
dihydrochloride salt (150 mg, 0.625 mmol),
3-amino-1-cyclopropyl-6,7-difluoro-8-methyl-1H-quinazoline-2,4-dione
(133 mg, 0.50 mmol), 1,1,3,3-tetramethylguanidine (0.25 mL, 2.0
mmol) in DMSO (0.5 mL) was heated to 100.degree. C. for 17 hours.
After cooling to room temperature, the reaction mixture was
subjected to preparative HPLC purification (Synergi Polar RP
column, 0.8 mL/min, gradient NH.sub.4.sup.+HCO.sub.2.sup.- pH
3.45:90% aqueous MeCN 90:10 to 1:1) to give firstly diastereomer A
followed by diastereomer B. Each diastereomer was further purified
by chromatography (CH.sub.2Cl.sub.2:MeOH:conc. NH.sub.3 95:5:0.5).
The diastereomers were separately taken up in HCl (2 mL of a 1.25
mol L.sup.-1 solution in MeOH), and concentrated under reduced
pressure to give diastereomer A (35 mg, 16%). HPLC 97% (99.5:0.5
mixture of diastereomers). .sup.1H NMR .quadrature.(D.sub.2O) 7.53
(d, 1H), 4.76 (m, 1H), 3.63-3.80 (m, 3H), 3.44-3.54 (m, 2H), 2.89
(m, 1H), 2.45 (s, 3H), 2.35 (m, 1H), 1.98 (m, 1H), 1.61 (s, 3H),
1.58 (s, 3H), 1.15 (m, 2H), 0.64 (m, 2H). LCMS (APCI.sup.+) 415
(100%, MH.sup.+). HRMS (FAB.sup.+) Calc. for
C.sub.21H.sub.28FN.sub.6O.sub.2 415.22578. Found 415.22696; and
diastereomer B (52 mg, 23%). HPLC 93% (99:1 mixture of
diastereomers). 1H NMR .quadrature.(D.sub.2O) 7.54 (d, 1H), 4.76
(m, 1H), 3.65-3.76 (m, 3H), 3.42-3.51 (m, 2H), 2.95 (m, 1H), 2.46
(s, 3H), 2.39 (m, 1H), 2.02 (m, 1H), 1.62 (s, 3H), 1.59 (s, 3H),
1.15 (m, 2H), 0.64 (m, 2H). LCMS (APCI.sup.+) 415 (100%, MH.sup.+).
HRMS (FAB.sup.+) Calc. for C.sub.21H.sub.28FN.sub.6O.sub.2
415.22578. Found 415.22697.
EXAMPLE 26
Preparation of
3-{[1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahy-
dro-quinazolin-7-yl)-4-fluoro-pyrrolidin-3-ylmethyl]-amino}-propionitrile
[0914] ##STR511##
[0915] The
3-Amino-7-(3-aminomethyl-4-fluoro-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-
-8-methoxy-1H-quinazoline-2,4-dione (WO2001053273A1) (0.101 g,
0.233 mmol) was taken up in methanol and charged with acrylonitrile
(0.1 mL). The solution was charged with 1 equivalent of
triethylamine. After 2 hours the solvent was removed in vacuo. The
residue was taken up in dichloromethane and charged with 2N
HCl/ether until cloudy. The resulting precipitate was collected via
filtration and washed with diethyl ether leaving 62 mg of the title
compound as the HCl salt (54% yield) MS (APCI+) m/z 435
(M+H).sup.+.
D. Pharmaceutical Formulations
EXAMPLE 27
[0916] The following illustrates representative pharmaceutical
dosage forms, containing a compound of Formula I ("Invention
Compound"), for therapeutic or prophylactic use in humans.
TABLE-US-00003 (i) Tablet mg/tablet `Invention Compound` 25.0
Lactose 50.0 Corn Starch (for mix) 10.0 Corn Starch (paste) 10.0
Magnesium Stearate (1%) 3.0 300.0
[0917] The invention compound, lactose, and corn starch (for mix)
are blended to uniformity. The corn starch (for paste) is suspended
in 200 mL of water and heated with stirring to form a paste. The
paste is used to granulate the mixed powders. The wet granules are
passed through a No. 8 hand screen and dried at 80.degree. C. The
dry granules are lubricated with the 1% magnesium stearate and
pressed into a tablet. Such tablets can be administered to a human
from one to four times a day for treatment of pathogenic bacterial
infections. TABLE-US-00004 (ii) Tablet mg/capsule `Invention
Compound 10.0 Colloidal Silicon Dioxide 1.5 Lactose 465.5
Pregelatinized Starch 120.0 Magnesium Stearate (1%) 3.0 600.0
[0918] TABLE-US-00005 (iii) Preparation for Oral Solution Amount
`Invention Compound` 400 mg Sorbitol Solution (70% N.F.) 40 mL
Sodium Benzoate 20 mg Saccharin 5 mg Cherry Flavor 20 mg Distilled
Water q.s. 100 mL
[0919] The sorbitol solution is added to 40 mL of distilled water,
and the invention compound is dissolved therein. The saccharin,
sodium benzoate, flavor, and dye are added and dissolved. The
volume is adjusted to 100 mL with distilled water. Each milliliter
of syrup contains 4 mg of invention compound.
(iv) Parenteral Solution
[0920] In a solution of 700 mL of propylene glycol and 200 mL of
water for injection is suspended 20 g of an invention compound.
After suspension is complete, the pH is adjusted to 6.5 with 1 N
hydrochloric acid, and the volume is made up to 1000 mL with water
for injection. The Formulation is sterilized, filled into 5.0 mL
ampoules each containing 2.0 mL, and sealed under nitrogen.
TABLE-US-00006 (v) Injection 1 (1 mg/mL) Amount `Invention
Compound` 1.0 Dibasic Sodium Phosphate 12.0 Monobasic Sodium
Phosphate 0.7 Sodium Chloride 4.5 N Sodium hydroxide solution q.s.
(pH adjustment to 7.0-7.5) Water for injection q.s. ad 1 mL
[0921] TABLE-US-00007 (vi) Injection 2 (10 mg/mL) Amount `Invention
Compound` 10.0 Dibasic Sodium Phosphate 1.1 Monobasic Sodium
Phosphate 0.3 Polyethylene glyco 400 200.0 N hydrochloric acid
solution q.s. (pH adjustment to 7.0-7.5) Water for injection q.s.
ad 1 mL
[0922] TABLE-US-00008 (vii) Injection 2 (10 mg/mL) Amount
`Invention Compound` 20.0 Oleic Acid 10.0
Trichloromonofluoromethane 5,000.0 Dichlorodifluoromethane 10,000.0
Dichlorotetrafluoroethane 5,000.0.
[0923] All patents, and patent documents are incorporated by
reference herein, as though individually incorporated by reference.
The invention and the manner and process of making and using it,
are now described in such full, clear, concise and exact terms as
to enable any person skilled in the art to which it pertains, to
make and use the same. It is to be understood that the foregoing
describes preferred embodiments of the present invention and that
modifications may be made therein without departing from the spirit
or scope of the present invention as set forth in the claims. To
particularly point out and distinctly claim the subject matter
regarded as invention, the following claims conclude this
specification.
* * * * *